Contraceptive compounds and methods

ABSTRACT

The invention provides a compound of formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrug thereof, wherein R 1 -R 6  have any of the values described in the specification, as well as compositions comprising a compound of formula (I). The compounds are useful as contraceptive agents.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Application No.63/184,014, filed on 4 May 2021 and to U.S. Provisional Application No.63/307,943, filed on 8 Feb. 2022, and to U.S. Provisional ApplicationNo. 63/326,524, filed on 1 Apr. 2022. The entire content of each ofthese United States Provisional applications is hereby incorporated byreference herein.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under HD093540 andHHSN275201300017C awarded by National Institutes of Health. Thegovernment has certain rights in the invention.

BACKGROUND

Despite making progress worldwide in providing birth control options tofamilies, the rate of unintended pregnancies, defined as both unwantedand mistimed pregnancies resulting from not using contraceptives orincorrect/inconsistent contraceptive use, remains high Bearak J., etal., 2018, Lancet Glob Health, 6, e380-e389). While rates of accidentalpregnancies have decreased, the unintended pregnancy rates in developednations are 45% and remain around 65% in developing nations Bearak J.,et al., 2018, Lancet Glob Health, 6, e380-e389). Approximately 56% ofall unintended pregnancies ended in abortion between 2010 and 2014-55%in developing nations and 59% in developed nations (Bearak J., et al.,2018, Lancet Glob Health, 6, e380-e389). There is thus a critical needfor additional approaches and resources for reversible contraception.While many reversible contraceptive methods are available to women, suchas hormonal birth control, emergency contraception, vaginal rings,cervical caps and spermicides, reversible methods for men are limited tocondoms and withdrawal. For an in-depth reviews and discussions of malecontraceptives, refer to Long J E., et al., 2019, Clin Chem, 65, 53-160;and Blithe D L., et al., 2016, Fertil Steril, 106, 1295-1302. There hasbeen interest in the use of testosterone and various testosterone estersas potential contraceptive agents (Armory J K., et al., 2006, Nat ClinPract Endocrinol Metab, 2, 32-41; and Page S T., et al., 2008, EndocrRev, 29, 465-493); however, testosterone alone does not completelysuppress sperm production, and there are ethnic differences in itsefficacy (Armory J K., et al., 2006, Nat Clin Pract Endocrinol Metab, 2,32-41; and Liu P Y., et al., 2008, J Clin Endocrinol Metab, 93,1774-1783). Supplementation of testosterone administration withprogestogens enhances the suppression of sperm production at lower dosesof testosterone. However, the effects of long-term exogenoustestosterone administration remain unclear. Treatment with testosteronehas been associated with several negative side effects, which caninclude cardiac toxicity (Xu L., et al., 2013, BMC Medicine, 11, 108)and liver damage (Westaby D., et al., 1977, Lancet, 310, 261-263). Themost common negative side effect was erythrocytosis, which has beenlinked to cerebrovascular disease (Coviello A D., et al., 2008, J ClinEndocrinol, 93, 914-919). Additionally, exogenous testosterone has beenshown to lower HDL cholesterol and increase hematocrit, hemoglobin, andthromboxane, all of which are associated with cardiovascular disease (XuL., et al., 2013, BMC Medicine, 11, 108). In addition to the moreserious side effects, patients also experienced weight gain, acne,injection-site pain, and mood changes like aggression and decreasedlibido (World Health Organization Task Force on Methods for theRegulation of Male Fertility, 1990, Lancet, 336, 955-959). In the studydescribed above, 2.2% of patients failed to reach the oligozoospermiathreshold, indicating that certain men are “non-responders” totestosterone treatment (World Health Organization Task Force on Methodsfor the Regulation of Male Fertility, 1990, Lancet, 336, 955-959).

Therefore, a need exists for an effective, non-steroid hormone-basedreversible male contraceptive that exhibits few if any side effects,health risks, and further complications. While hormone therapy relies oninterrupting the spermatogenic process, there are far more targets fornon-hormonal-based therapies that can be pursued (Blithe D., 2008,Contraception, 78, S23-S27). Non-hormonal male contraceptive approachesinvolve targeting proteins that affect either sperm production or spermfunction and are anticipated to have minimal side effects, depending onthe specificity and potency of inhibitors for the target protein.

SUMMARY

An effective, non-steroid hormone-based reversible male contraceptivethat exhibits few if any side effects, health risks, or furthercomplications has been identified. Accordingly, in one aspect thepresent invention provides a retinoic acid receptor-α antagonistcompound of the invention, which is a compound of formula (I):

or a pharmaceutically-acceptable salt, stereoisomer, solvate, or prodrugthereof, wherein:

R¹ is H, C₁-C₃ alkyl, or haloC₁-C₃ alkyl;

R² is H, C₁-C₃ alkyl, or haloC₁-C₃ alkyl;

R³ is C₆-C₁₀ aryl, 5-10 membered heteroaryl, C₆-C₁₀ arylC₁-C₃ alkyl, or5-10 membered heteroarylC₁-C₃ alkyl, wherein any C₆-C₁₀ aryl, 5-10membered heteroaryl, C₆-C₁₀ arylC₁-C₃ alkyl, and 5-10 memberedheteroarylC₁-C₃ alkyl is optionally substituted with one or more groupsindependently selected from halo, cyano, nitro, carboxy, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ alkanoyl, C₁-C₆ alkanoyloxy, C₁-C₆ alkoxycarbonyl,—NR^(a)R^(b), or —C(═O)NR^(c)R^(d), wherein any C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ alkanoyl, C₁-C₆ alkanoyloxy, and C₁-C₆ alkoxycarbonyl isoptionally substituted with one or more groups independently selectedfrom halo;

R⁴ is C₆-C₁₀ aryl, 5-10 membered heteroaryl, C₆-C₁₀ arylC₁-C₃ alkyl, or5-10 membered heteroarylC₁-C₃ alkyl, wherein any C₆-C₁₀ aryl, 5-10membered heteroaryl, C₆-C₁₀ arylC₁-C₃ alkyl, and 5-10 memberedheteroarylC₁-C₃ alkyl is substituted with carboxy and is furtheroptionally substituted with one or more groups independently selectedfrom halo, hydroxy, cyano, nitro, carboxy, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ alkanoyl, C₁-C₆ alkanoyloxy, C₁-C₆ alkoxycarbonyl, —NR^(e)R^(f),or —C(═O)NR^(g)R^(h), wherein any C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆alkanoyl, C₁-C₆ alkanoyloxy, and C₁-C₆ alkoxycarbonyl is optionallysubstituted with one or more groups independently selected from halo;

R⁵ is H, C₁-C₃ alkyl, hydroxy, C₁-C₃ alkoxy, halo or haloC₁-C₃ alkyl;

R⁶ is H, C₁-C₃ alkyl, hydroxy, C₁-C₃ alkoxy, halo or haloC₁-C₃ alkyl;

each R^(a) and R^(b) is independently selected from the group consistingof H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, and(C₃-C₆)cycloalkyl(C₁-C₆)alkyl; or R^(a) and R^(b) together with thenitrogen to which they are attached form an aziridino, azetidino,morpholino, piperazino, pyrrolidino or piperidino ring, which ring isoptionally substituted with one or more groups independently selectedfrom C₁-C₆ alkyl and haloC₁-C₆ alkyl;

each R^(c) and R^(d) is independently selected from the group consistingof H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, and(C₃-C₆)cycloalkyl(C₁-C₆)alkyl; or R^(c) and R^(d) together with thenitrogen to which they are attached form an aziridino, azetidino,morpholino, piperazino, pyrrolidino or piperidino ring, which ring isoptionally substituted with one or more groups independently selectedfrom C₁-C₆ alkyl and haloC₁-C₆ alkyl;

each R^(e) and R^(f) is independently selected from the group consistingof H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, and(C₃-C₆)cycloalkyl(C₁-C₆)alkyl; or R^(e) and R^(f) together with thenitrogen to which they are attached form an aziridino, azetidino,morpholino, piperazino, pyrrolidino or piperidino ring, which ring isoptionally substituted with one or more groups independently selectedfrom C₁-C₆ alkyl and haloC₁-C₆ alkyl; and

each R^(g) and R^(h) is independently selected from the group consistingof H, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, and(C₃-C₆)cycloalkyl(C₁-C₆)alkyl; or R^(g) and R^(h) together with thenitrogen to which they are attached form an aziridino, azetidino,morpholino, piperazino, pyrrolidino or piperidino ring, which ring isoptionally substituted with one or more groups independently selectedfrom C₁-C₆ alkyl and haloC₁-C₆ alkyl.

The invention also provides a pharmaceutical composition comprising acompound of formula (I) or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.

In another embodiment, the invention provides a method to reduce spermcount in a male subject, comprising administering a compound of formula(I) or a pharmaceutically acceptable salt thereof to the male subject(e.g., a human).

In another embodiment, the invention provides a method to producereversible infertility in a male subject, comprising administering acompound of formula (I) or a pharmaceutically acceptable salt thereof tothe male mammal (e.g., a human).

In another embodiment, the invention provides a method to reduce thelikelihood of conception following intercourse between a male subjectand a female subject, comprising administering a compound of formula (I)or a pharmaceutically acceptable salt thereof to the male subject (e.g.,a human) prior to the intercourse.

In another embodiment, the invention provides a method for treating adisease or condition associated with RAR alpha activity in a subjectwherein antagonism of RAR alpha is indicated, comprising administering acompound of formula (I) or a pharmaceutically acceptable salt thereof tothe mammal.

In another embodiment, the invention provides a method for selectivelyantagonizing RAR alpha over RAR beta and RAR gamma in a subject,comprising administering a compound of formula (I) or a pharmaceuticallyacceptable salt thereof to the subject.

In another embodiment, the invention provides a method for selectivelyantagonizing RAR alpha over RAR beta and RAR gamma, comprisingcontacting RAR alpha, RAR beta, and RAR gamma in vitro with a compoundof formula (I) or a salt thereof.

In another embodiment, the invention provides a compound of formula (I)or a pharmaceutically acceptable salt thereof for use in medicaltherapy.

In another embodiment, the invention provides a compound of formula (I)or a pharmaceutically acceptable salt thereof to reduce sperm count in amale subject.

In another embodiment, the invention provides a compound of formula (I)or a pharmaceutically acceptable salt thereof to produce reversibleinfertility in a male subject.

In another embodiment, the invention provides a compound of formula (I)or a pharmaceutically acceptable salt thereof to reduce the likelihoodof conception following intercourse between a male subject and a femalesubject.

In another embodiment, the invention provides a compound of formula (I)or a pharmaceutically acceptable salt thereof to treating a disease orcondition associated with RAR alpha activity.

In another embodiment, the invention provides a compound of formula (I)or a pharmaceutically acceptable salt thereof to selectively antagonizeRAR alpha over RAR beta and RAR gamma in vitro.

In another embodiment, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof to prepare amedicament to reduce sperm count in a male subject.

In another embodiment, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof to prepare amedicament to produce reversible infertility in a male subject.

In another embodiment, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof to prepare amedicament to reduce the likelihood of conception following intercoursebetween a male subject and a female subject.

In another embodiment, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof to prepare amedicament treat a disease or condition associated with RAR alphaactivity in a subject.

In another embodiment, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof to prepare amedicament to selectively antagonize RAR alpha over RAR beta and RARgamma in a subject.

In another embodiment, the invention provides a kit comprising packagingmaterial that contains a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, and instructions for use of the compound offormula (I) or a pharmaceutically acceptable salt thereof as acontraceptive (e.g., to reduce sperm count in a male subject, to producereversible infertility in a male subject, and/or to reduce thelikelihood of conception or eliminate the likelihood of conception).

In another embodiment, the invention provides a method to reduce spermcount in a male subject, comprising orally administering a compound thatis a selective antagonist of RAR alpha or a pharmaceutically acceptablesalt thereof to the male subject (e.g., a human).

In another embodiment, the invention provides a method to producereversible infertility in a male subject, comprising administering acompound that is a selective antagonist of RAR alpha or apharmaceutically acceptable salt thereof to the male subject (e.g., ahuman).

In another embodiment, the invention provides a method to reduce thelikelihood of conception following intercourse between a male subjectand a female subject, comprising administering a compound that is aselective antagonist of RAR alpha or a pharmaceutically acceptable saltthereof to the male subject (e.g., a human) prior to the intercourse.

In another embodiment, the invention provides a method for treating adisease or condition associated with RAR alpha activity in a subjectwherein antagonism of RAR alpha is indicated, comprising administering acompound that is a selective antagonist of RAR alpha or apharmaceutically acceptable salt thereof to the subject.

In another embodiment, the invention provides a compound that is orallyactive and a selective antagonist of RAR alpha or a pharmaceuticallyacceptable salt thereof to reduce sperm count in a male subject.

In another embodiment, the invention provides a compound that is orallyactive and a selective antagonist of RAR alpha or a pharmaceuticallyacceptable salt thereof to produce reversible infertility in a malesubject.

In another embodiment, the invention provides a compound that is orallyactive and a selective antagonist of RAR alpha or a pharmaceuticallyacceptable salt thereof to reduce the likelihood of conception followingintercourse between a male subject and a female subject.

In another embodiment, the invention provides a compound that is orallyactive and a selective antagonist of RAR alpha or a pharmaceuticallyacceptable salt thereof to treating a disease or condition associatedwith RAR alpha activity.

In another embodiment, the invention provides the use of a compound thatis orally active and a selective antagonist of RAR alpha or apharmaceutically acceptable salt thereof to prepare a medicament toreduce sperm count in a male subject.

In another embodiment, the invention provides the use of a compound thatis orally active and a selective antagonist of RAR alpha or apharmaceutically acceptable salt thereof to prepare a medicament toproduce reversible infertility in a male subject.

In another embodiment, the invention provides the use of a compound thatis orally active and a selective antagonist of RAR alpha or apharmaceutically acceptable salt thereof to prepare a medicament toreduce the likelihood of conception following intercourse between a malesubject and a female subject.

In another embodiment, the invention provides the use of a compound thatis orally active and a selective antagonist of RAR alpha or apharmaceutically acceptable salt thereof to prepare a medicament treat adisease or condition associated with RAR alpha activity in a subject.

The invention also provides processes and intermediates disclosed hereinthat are useful for preparing a compound of formula (I) or apharmaceutically-acceptable salt, stereoisomer, solvate, or prodrugthereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows distribution data for the compound of Example 1 fromExample 14.

FIG. 2 shows an experimental scheme for testing the effect of thecompound of Example 1 on male fertility (identified as GPHR-00354529)from Example 14.

FIG. 3 shows that the administration of the compound of Example 1(identified as GPHR-00354529) to male mice at 10 mg/kg for four weeksresults in infertility two weeks post administration from Example 16.

FIG. 4 shows that the administration of the compound of Example 1(identified as GPHR-00354529) to male mice at 20 mg/kg for two weeksresults in infertility four weeks post administration from Example 16.

FIG. 5 shows that the administration of the compound of Example 1(identified as GPHR-00354529) to male mice at 10 mg/kg for four weeksresults in infertility and that fertility is recovered four to six weekspost administration from Example 16.

FIG. 6 shows that administration of the compound of Example 1(identified as GPHR-00354529) to male mice at 20 mg/kg for two weeksresulted in infertility and that fertility is recovered six weeks postadministration from Example 16.

FIG. 7 shows that 10 mg/kg of the compound of Example 1 reversiblyreduces sperm counts in mice. 25 male CD-1 mice were dosed with 10mg/kg/day (grey bars) for 4 weeks. Epididymal sperm counts were assessedonce per week as of week 3 and compared to control (white bars). Shownare means±SD of absolute sperm counts from 5 mice per time point.***p<0.001, ****p<0.0001. See Example 19.

FIG. 8 shows that 7.5 mg/kg of the compound of Example 1 reversiblyreduces sperm counts in mice. 40 male CD-1 mice were dosed with 7.5mg/kg/day (greybars) for 4 weeks. Epididymal sperm counts were assessedonce per week as of week 3 and compared to control (white bars). Shownare means±SD of absolute sperm counts from 10 mice per time point.***p<0.001, ****p<0.0001. See Example 19.

FIG. 9 shows that the compound of Example 1 does not change free serumtestosterone levels in mice. 40 male CD-1 mice were dosed with 7.5mg/kg/day (grey bars) for 4 weeks. Free serum testosterone levels wereassessed with ELISA once per week as of week 3 and compared to control(white bars). Shown are means±SD from 10 mice per time point. SeeExample 19.

FIG. 10 Three male cynomolgus macaques were dosed at 5 mg/kg/day for 30days followed by 7.5 mg/kg/day for 1 week with the compound ofExample 1. As of Day 38, the animals have been in recovery (ongoing).Sperm counts were assessed from fresh semen samples collected withelectro-ejaculation at the indicated time points. Shown are sperm countsof each animal (dark grey lines with triangle, circle and diamondsymbols) and means±SD (black line with square symbol). The horizontaldashed line indicates reported sperm counts of non-breeders. See Example19.

FIG. 11 shows that the compound of Example 1 impairs the germinalepithelium in dog and rat testis. 2 male Beagle dogs and 5 male SD ratswere dosed with 25 mg/kg/day for 14 days. On Day 15, animals wereeuthanized to harvest organs for histopathology. Shown arerepresentative images. See Example 19.

DETAILED DESCRIPTION

The following definitions are used, unless otherwise described: halo orhalogen is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denoteboth straight and branched groups, but reference to an individualradical such as propyl embraces only the straight chain radical, abranched chain isomer such as isopropyl being specifically referred to.

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbonradical, having the number of carbon atoms designated (i.e., C₁-C₈ meansone to eight carbons). Examples include (C₁-C₆)alkyl, (C₁-C₃)alkyl,(C₂-C₆)alkyl and (C₃-C₆)alkyl. Examples of alkyl groups include methyl,ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl,n-pentyl, n-hexyl, n-heptyl, n-octyl, and higher homologs and isomers.

The term “alkoxy” refers to an alkyl group attached to the remainder ofthe molecule via an oxygen atom (“oxy”).

The term “alkanoyl” refers to an alkyl group attached to the remainderof the molecule via a carbonyl C(═O)— group.

The term “cycloalkyl” refers to a saturated or partially unsaturated(non-aromatic) all carbon ring having 3 to 8 carbon atoms (i.e.,(C₃-C₈)carbocycle). The term also includes multiple condensed, saturatedall carbon ring systems (e.g., ring systems comprising 2, 3 or 4carbocyclic rings). Accordingly, carbocycle includes multicycliccarbocycles such as a bicyclic carbocycles (e.g., bicyclic carbocycleshaving about 3 to 15 carbon atoms, about 6 to 15 carbon atoms, or 6 to12 carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane),and polycyclic carbocycles (e.g tricyclic and tetracyclic carbocycleswith up to about 20 carbon atoms). The rings of the multiple condensedring system can be connected to each other via fused, spiro and bridgedbonds when allowed by valency requirements. For example, multicycliccarbocycles can be connected to each other via a single carbon atom toform a spiro connection (e.g., spiropentane, spiro[4,5]decane, etc), viatwo adjacent carbon atoms to form a fused connection (e.g., carbocyclessuch as decahydronaphthalene, norsabinane, norcarane) or via twonon-adjacent carbon atoms to form a bridged connection (e.g.,norbornane, bicyclo[2.2.2]octane, etc). Non-limiting examples ofcycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,bicyclo[2.2.1]heptane, pinane, and adamantane.

The term “aryl” as used herein refers to a single all carbon aromaticring or a multiple condensed all carbon ring system wherein at least oneof the rings is aromatic. For example, in certain embodiments, an arylgroup has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbonatoms, or 6 to 10 carbon atoms. Aryl includes a phenyl radical. Arylalso includes multiple condensed carbon ring systems (e.g., ring systemscomprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in whichat least one ring is aromatic and wherein the other rings may bearomatic or not aromatic (i.e., cycloalkyl). The rings of the multiplecondensed ring system can be connected to each other via fused, spiroand bridged bonds when allowed by valency requirements. It is to beunderstood that the point of attachment of a multiple condensed ringsystem, as defined above, can be at any position of the ring systemincluding an aromatic or a carbocycle portion of the ring. Non-limitingexamples of aryl groups include, but are not limited to, phenyl,indenyl, indanyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl,and the like.

The term “heterocycle” refers to a single saturated or partiallyunsaturated ring that has at least one atom other than carbon in thering, wherein the atom is selected from the group consisting of oxygen,nitrogen and sulfur; the term also includes multiple condensed ringsystems that have at least one such saturated or partially unsaturatedring, which multiple condensed ring systems are further described below.Thus, the term includes single saturated or partially unsaturated rings(e.g., 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 carbon atomsand from about 1 to 3 heteroatoms selected from the group consisting ofoxygen, nitrogen and sulfur in the ring. The sulfur and nitrogen atomsmay also be present in their oxidized forms. Exemplary heterocyclesinclude but are not limited to azetidinyl, tetrahydrofuranyl andpiperidinyl. The term “heterocycle” also includes multiple condensedring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein asingle heterocycle ring (as defined above) can be condensed with one ormore groups selected from cycloalkyl, aryl, and heterocycle to form themultiple condensed ring system. The rings of the multiple condensed ringsystem can be connected to each other via fused, spiro and bridged bondswhen allowed by valency requirements. It is to be understood that theindividual rings of the multiple condensed ring system may be connectedin any order relative to one another. It is also to be understood thatthe point of attachment of a multiple condensed ring system (as definedabove for a heterocycle) can be at any position of the multiplecondensed ring system including a heterocycle, aryl and carbocycleportion of the ring. In one embodiment the term heterocycle includes a3-15 membered heterocycle. In one embodiment the term heterocycleincludes a 3-10 membered heterocycle. In one embodiment the termheterocycle includes a 3-8 membered heterocycle. In one embodiment theterm heterocycle includes a 3-7 membered heterocycle. In one embodimentthe term heterocycle includes a 3-6 membered heterocycle. In oneembodiment the term heterocycle includes a 4-6 membered heterocycle. Inone embodiment the term heterocycle includes a 3-10 membered monocyclicor bicyclic heterocycle comprising 1 to 4 heteroatoms. In one embodimentthe term heterocycle includes a 3-8 membered monocyclic or bicyclicheterocycle comprising 1 to 3 heteroatoms. In one embodiment the termheterocycle includes a 3-6 membered monocyclic heterocycle comprising 1to 2 heteroatoms. In one embodiment the term heterocycle includes a 4-6membered monocyclic heterocycle comprising 1 to 2 heteroatoms. Exemplaryheterocycles include, but are not limited to aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl,tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl,benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl,2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl,spiro[cyclopropane-1,1′-isoindolinyl]-3′-one, isoindolinyl-1-one,2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one imidazolidine,pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin,dioxolane, phthalimide, and 1,4-dioxane.

The term “heteroaryl” as used herein refers to a single aromatic ringthat has at least one atom other than carbon in the ring, wherein theatom is selected from the group consisting of oxygen, nitrogen andsulfur; “heteroaryl” also includes multiple condensed ring systems thathave at least one such aromatic ring, which multiple condensed ringsystems are further described below. Thus, “heteroaryl” includes singlearomatic rings of from about 1 to 6 carbon atoms and about 1-4heteroatoms selected from the group consisting of oxygen, nitrogen andsulfur. The sulfur and nitrogen atoms may also be present in an oxidizedform provided the ring is aromatic. Exemplary heteroaryl ring systemsinclude but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.“Heteroaryl” also includes multiple condensed ring systems (e.g., ringsystems comprising 2, 3 or 4 rings) wherein a heteroaryl group, asdefined above, is condensed with one or more rings selected fromcycloalkyl, aryl, heterocycle, and heteroaryl. It is to be understoodthat the point of attachment for a heteroaryl or heteroaryl multiplecondensed ring system can be at any suitable atom of the heteroaryl orheteroaryl multiple condensed ring system including a carbon atom and aheteroatom (e.g., a nitrogen). Exemplary heteroaryls include but are notlimited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl,pyrazolyl, thienyl, indolyl, imidazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl,quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl,quinoxalyl, and quinazolyl.

The term “alkoxycarbonyl” as used herein refers to a group(alkyl)-O—C(═O)—, wherein the term alkyl has the meaning defined herein.

The term “alkanoyloxy” as used herein refers to a group(alkyl)-C(═O)—O—, wherein the term alkyl has the meaning defined herein.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

As used herein, the term “protecting group” refers to a substituent thatis commonly employed to block or protect a particular functional groupon a compound. For example, an “amino-protecting group” is a substituentattached to an amino group that blocks or protects the aminofunctionality in the compound. Suitable amino-protecting groups includeacetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ)and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Suitable protectinggroups include acetyl and silyl. A “carboxy-protecting group” refers toa substituent of the carboxy group that blocks or protects the carboxyfunctionality. Common carboxy-protecting groups includephenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyland the like. For a general description of protecting groups and theiruse, see P. G. M. Wuts and T. W. Greene, Greene's Protective Groups inOrganic Synthesis 4^(th) edition, Wiley-Interscience, New York, 2006.

As used herein a wavy line “

” that intersects a bond in a chemical structure indicates the point ofattachment of the bond that the wavy bond intersects in the chemicalstructure to the remainder of a molecule.

The terms “treat”, “treatment”, or “treating” to the extent it relatesto a disease or condition includes inhibiting the disease or condition,eliminating the disease or condition, and/or relieving one or moresymptoms of the disease or condition. The terms “treat”, “treatment”, or“treating” also refer to both therapeutic treatment and/or prophylactictreatment or preventative measures, wherein the object is to prevent orslow down (lessen) an undesired physiological change or disorder. Forexample, beneficial or desired clinical results include, but are notlimited to, alleviation of symptoms, diminishment of extent of diseaseor disorder, stabilized (i.e., not worsening) state of disease ordisorder, delay or slowing of disease progression, amelioration orpalliation of the disease state or disorder, and remission (whetherpartial or total), whether detectable or undetectable. “Treat”,“treatment”, or “treating,” can also mean prolonging survival ascompared to expected survival if not receiving treatment. Those in needof treatment include those already with the disease or disorder as wellas those prone to have the disease or disorder or those in which thedisease or disorder is to be prevented. In one embodiment “treat”,“treatment”, or “treating” does not include preventing or prevention,

The phrase “therapeutically effective amount” or “effective amount”includes but is not limited to an amount of a compound of the that (i)treats or prevents the particular disease, condition, or disorder, (ii)attenuates, ameliorates, or eliminates one or more symptoms of theparticular disease, condition, or disorder, or (iii) prevents or delaysthe onset of one or more symptoms of the particular disease, condition,or disorder described herein.

The term “subject” as used herein refers to any individual or patient towhich the subject methods are performed. Generally, the subject is amammal, specifically human, although as will be appreciated by those inthe art, the subject may be an animal. Thus other animals, includingvertebrate such as rodents (including mice, rats, hamsters and guineapigs), cats, dogs, rabbits, farm animals including cows, horses, goats,sheep, pigs, chickens, etc., and primates (including monkeys,chimpanzees, orangutans and gorillas) are included within the definitionof subject. In one embodiment the subject is a mammalian subject. In oneembodiment, the subject is a human subject.

The term “mammal” as used herein refers to humans, higher non-humanprimates, rodents, domestic, cows, horses, pigs, sheep, dogs and cats.In one embodiment, the mammal is a human.

The term “selective antagonist of RAR alpha” refers to a compound thathas at least 2, 5, or 10 fold greater antagonist activity at RAR alphacompared to its activity at either RAR beta or RAR gamma. In oneembodiment, the term “selective agonist of RAR alpha” refers to acompound that has at least 2, 5, or 10 fold greater antagonist activityat RAR alpha compared to its activity at both RAR beta and RAR gamma.

The compounds disclosed herein can also exist as tautomeric isomers incertain cases. Although only one delocalized resonance structure may bedepicted, all such forms are contemplated within the scope of theinvention.

It is understood by one skilled in the art that this invention alsoincludes any compound claimed that may be enriched at any or all atomsabove naturally occurring isotopic ratios with one or more isotopes suchas, but not limited to, deuterium (²H or D). As a non-limiting example,a —CH₃ group may be substituted with —CD₃.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention can contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand l or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or 1 meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer can also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which canoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase.

When a bond in a compound formula herein is drawn in anon-stereochemical manner (e.g. flat), the atom to which the bond isattached includes all stereochemical possibilities. When a bond in acompound formula herein is drawn in a defined stereochemical manner(e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understoodthat the atom to which the stereochemical bond is attached is enrichedin the absolute stereoisomer depicted unless otherwise noted. In oneembodiment, the compound may be at least 51% the absolute stereoisomerdepicted. In another embodiment, the compound may be at least 60% theabsolute stereoisomer depicted. In another embodiment, the compound maybe at least 80% the absolute stereoisomer depicted. In anotherembodiment, the compound may be at least 90% the absolute stereoisomerdepicted. In another embodiment, the compound may be at least 95 theabsolute stereoisomer depicted. In another embodiment, the compound maybe at least 99% the absolute stereoisomer depicted.

Specific values listed below for radicals, substituents, and ranges, arefor illustration only; they do not exclude other defined values or othervalues within defined ranges for the radicals and substituents. It is tobe understood that two or more values may be combined. It is also to beunderstood that the values listed herein below (or subsets thereof) canbe excluded.

Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl; (C₁-C₆)alkoxycan be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy,sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C₁-C₆)alkanoyl can beacetyl, propanoyl or butanoyl; aryl can be phenyl, indenyl, or naphthyl;and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl,isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl,tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or itsN-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or itsN-oxide).

A specific value for R¹ is C₁-C₃ alkyl.

A specific value for R¹ is methyl.

A specific value for R² is C₁-C₃ alkyl.

A specific value for R² is methyl.

A specific value for R³ is C₆-C₁₀ aryl that is optionally substitutedwith one or more (e.g., 1, 2, 3, or 4) groups independently selectedfrom halo, cyano, nitro, carboxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆alkanoyl, C₁-C₆ alkanoyloxy, C₁-C₆ alkoxycarbonyl, —NR^(a)R^(b), and—C(═O)NR^(c)R^(d), wherein any C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆alkanoyl, C₁-C₆ alkanoyloxy, and C₁-C₆ alkoxycarbonyl is optionallysubstituted with one or more groups independently selected from halo.

A specific value for R³ is phenyl that is optionally substituted withone or more (e.g., 1, 2, 3, or 4) groups independently selected fromhalo, cyano, nitro, carboxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkanoyl,C₁-C₆ alkanoyloxy, C₁-C₆ alkoxycarbonyl, —NR^(a)R^(b), and—C(═O)NR^(c)R^(d), wherein any C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆alkanoyl, C₁-C₆ alkanoyloxy, and C₁-C₆ alkoxycarbonyl is optionallysubstituted with one or more groups independently selected from halo.

A specific value for R³ is C₆-C₁₀ aryl that is optionally substitutedwith one or more (e.g., 1, 2, 3, or 4) groups independently selectedfrom C₁-C₆ alkyl that is optionally substituted with one or more groupsindependently selected from halo.

A specific value for R³ is phenyl that is optionally substituted withone or more (e.g., 1, 2, 3, or 4) groups independently selected fromC₁-C₆ alkyl that is optionally substituted with one or more groupsindependently selected from halo.

A specific value for R³ is C₆-C₁₀ aryl that is substituted with C₁-C₆alkyl.

A specific value for R³ is phenyl that is substituted with C₁-C₆ alkyl.

A specific value for R³ is 4-methylphenyl.

A specific value for R⁴ is C₆-C₁₀ aryl, 5-10 membered heteroaryl, C₆-C₁₀arylC₁-C₃ alkyl, or 5-10 membered heteroarylC₁-C₃ alkyl, wherein anyC₆-C₁₀ aryl, 5-10 membered heteroaryl, C₆-C₁₀ arylC₁-C₃ alkyl, and 5-10membered heteroarylC₁-C₃ alkyl is substituted with carboxy and isfurther optionally substituted with one or more groups independentlyselected from halo, cyano, nitro, carboxy, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ alkanoyl, C₁-C₆ alkanoyloxy, C₁-C₆ alkoxycarbonyl, —NR^(e)R^(f),or —C(═O)NR^(g)R^(h), wherein any C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆alkanoyl, C₁-C₆ alkanoyloxy, and C₁-C₆ alkoxycarbonyl is optionallysubstituted with one or more groups independently selected from halo;

A specific value for R⁴ is C₆-C₁₀ aryl that is substituted with carboxyand that is further optionally substituted with one or more (e.g., 1, 2,3, or 4) groups independently selected from halo, cyano, nitro, carboxy,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkanoyl, C₁-C₆ alkanoyloxy, C₁-C₆alkoxycarbonyl, —NR^(a)R^(b), and —C(═O)NR^(c)R^(d), wherein any C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ alkanoyl, C₁-C₆ alkanoyloxy, and C₁-C₆alkoxycarbonyl is optionally substituted with one or more groupsindependently selected from halo.

A specific value for R⁴ is phenyl that is substituted with carboxy andthat is further optionally substituted with one or more (e.g., 1, 2, 3,or 4) groups independently selected from halo, cyano, nitro, carboxy,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkanoyl, C₁-C₆ alkanoyloxy, C₁-C₆alkoxycarbonyl, —NR^(a)R^(b), and —C(═O)NR^(c)R^(d), wherein any C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ alkanoyl, C₁-C₆ alkanoyloxy, and C₁-C₆alkoxycarbonyl is optionally substituted with one or more groupsindependently selected from halo.

A specific value for R⁴ is C₆-C₁₀ aryl that is substituted with carboxyand that is further optionally substituted with one or more (e.g., 1, 2,3, or 4) groups independently selected from C₁-C₆ alkyl that isoptionally substituted with one or more groups independently selectedfrom halo.

A specific value for R⁴ is phenyl that is substituted with carboxy andthat is further optionally substituted with one or more (e.g., 1, 2, 3,or 4) groups independently selected from C₁-C₆ alkyl that is optionallysubstituted with one or more groups independently selected from halo.

A specific value for R⁴ is C₆-C₁₀ aryl that is substituted with carboxy.

A specific value for R⁴ is phenyl that is substituted with carboxy.

A specific value for R⁴ is 4-carboxyphenyl.

A specific value for R⁵ is H.

A specific value for R⁶ is H.

A specific compound or salt is a compound of formula (Ia):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrugthereof.

A specific compound or salt is a compound of formula (Ib):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrugthereof.

A specific compound or salt is a compound of formula (Ic):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrugthereof.

A specific compound or salt is a compound of formula (Id):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrugthereof.

A specific compound or salt is:

or a pharmaceutically acceptable salt thereof.

A specific compound or salt is:

or a pharmaceutically acceptable salt thereof.

A specific compound, pharmaceutically acceptable salt, stereoisomer,solvate, or prodrug is selected from the group consisting of:

and pharmaceutically acceptable salts, stereoisomers, solvates, andprodrugs thereof.

Processes for preparing compounds of formula I are provided as furtherembodiments of the invention and are illustrated by the followingprocedures in which the meanings of the generic radicals are as givenabove unless otherwise qualified.

In cases where compounds are sufficiently basic or acidic, a salt of acompound of formula I can be useful as an intermediate for isolating orpurifying a compound of formula I. Additionally, administration of acompound of formula I as a pharmaceutically acceptable acid or base saltmay be appropriate. Examples of pharmaceutically acceptable salts areorganic acid addition salts formed with acids which form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso be formed, including hydrochloride, sulfate, nitrate, bicarbonate,and carbonate salts.

Salts may be obtained using standard procedures well known in the art,for example by reacting a sufficiently basic compound such as an aminewith a suitable acid affording a physiologically acceptable anion.Alkali metal (for example, sodium, potassium or lithium) or alkalineearth metal (for example calcium) salts of carboxylic acids can also bemade.

The compounds of formula (I) can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humansubject, in a variety of forms adapted to the chosen route ofadministration, i.e., orally or parenterally, by intravenous,intramuscular, topical or subcutaneous routes. The pharmaceuticalcompositions of the invention can comprise one or more excipients. Whenused in combination with the pharmaceutical compositions of theinvention the term “excipients” refers generally to an additionalingredient that is combined with the compound of formula (I) or thepharmaceutically acceptable salt thereof to provide a correspondingcomposition. For example, when used in combination with thepharmaceutical compositions of the invention the term “excipients”includes, but is not limited to: carriers, binders, disintegratingagents, lubricants, sweetening agents, flavoring agents, coatings,preservatives, and dyes.

As used herein, “pharmaceutical composition” refers to a formulationcomprising an active ingredient, and optionally a pharmaceuticallyacceptable carrier, diluent or excipient. The term “active ingredient”can interchangeably refer to an “effective ingredient” and is meant torefer to any agent that is capable of inducing a sought-after effectupon administration. Examples of active ingredient include, but are notlimited to, chemical compound, drug, therapeutic agent, small molecule,etc.

The pharmaceutical compositions of the invention can comprise one ormore excipients. When used in combination with the pharmaceuticalcompositions of the invention the term “excipients” refers generally toan additional ingredient that is combined with the compound of formula(I) or the pharmaceutically acceptable salt thereof to provide acorresponding composition. For example, when used in combination withthe pharmaceutical compositions of the invention the term “excipients”includes, but is not limited to: carriers, binders, disintegratingagents, lubricants, sweetening agents, flavoring agents, coatings,preservatives, and dyes.

By “pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof, nor to theactivity of the active ingredient of the formulation. Pharmaceuticallyacceptable carriers, excipients or stabilizers are well known in theart, for example Remington's Pharmaceutical Sciences, 16th edition,Osol, A. Ed. (1980). Pharmaceutically acceptable carriers, excipients,or stabilizers are nontoxic to recipients at the dosages andconcentrations employed, and may include buffers such as phosphate,citrate, and other organic acids; antioxidants including ascorbic acidand methionine; preservatives (such as octadecyldimethylbenzyl ammoniumchloride; hexamethonium chloride; benzalkonium chloride, benzethoniumchloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methylor propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; andm-cresol); low molecular weight (less than about 10 residues)polypeptides; proteins, such as serum albumin, gelatin, orimmunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone;amino acids such as glycine, glutamine, asparagine, histidine, arginine,or lysine; monosaccharides, disaccharides, and other carbohydratesincluding glucose, mannose, or dextrins; chelating agents such as EDTA;sugars such as sucrose, mannitol, trehalose or sorbitol; salt-formingcounter-ions such as sodium; metal complexes (for example, Zn-proteincomplexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ orpolyethylene glycol (PEG). Examples of carrier include, but are notlimited to, liposome, nanoparticles, ointment, micelles, microsphere,microparticle, cream, emulsion, and gel. Examples of excipient include,but are not limited to, anti-adherents such as magnesium stearate,binders such as saccharides and their derivatives (sucrose, lactose,starches, cellulose, sugar alcohols and the like) protein like gelatinand synthetic polymers, lubricants such as talc and silica, andpreservatives such as antioxidants, vitamin A, vitamin E, vitamin C,retinyl palmitate, selenium, cysteine, methionine, citric acid, sodiumsulfate and parabens. Examples of diluent include, but are not limitedto, water, alcohol, saline solution, glycol, mineral oil and dimethylsulfoxide (DMSO).

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle orexcipient such as an inert diluent or an assimilable edible carrier.They may be enclosed in hard or soft shell gelatin capsules, may becompressed into tablets, or may be incorporated directly with the foodof the subject's diet. For oral therapeutic administration, the activecompound may be combined with one or more pharmaceutically acceptableexcipients and used in the form of ingestible tablets, buccal tablets,troches, capsules, elixirs, suspensions, syrups, wafers, and the like.Such compositions and preparations should contain at least 0.1% ofactive compound. The percentage of the compositions and preparationsmay, of course, be varied and may conveniently be between about 2 toabout 60% of the weight of a given unit dosage form. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze-drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the compounds of formula (I) to the skin are known to the art;for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S.Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman(U.S. Pat. No. 4,820,508).

Useful dosages of the compounds of formula (I) can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

The amount of the compound, or an active salt or derivative thereof,required for use in treatment will vary not only with the particularsalt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition of the subject orpatient and will be ultimately at the discretion of the attendantphysician or clinician.

The dose of a compound of formula (I) to be administered to a subjectcan optionally range from about 0.0001 mg/kg to about 100 mg/kg, about0.01 mg/kg to about 5 mg/kg, about 0.15 mg/kg to about 3 mg/kg, 0.5mg/kg to about 2 mg/kg and about 1 mg/kg to about 2 mg/kg of thesubject's body weight. In other aspects, the dose ranges from about 100mg/kg to about 5 g/kg, about 500 mg/kg to about 2 mg/kg and about 750mg/kg to about 1.5 g/kg of the subject's body weight. For example,depending on the type and severity of the disease, about 1 μg/kg to 15mg/kg (e.g., 0.1-20 mg/kg) of compound is a candidate dosage foradministration to the subject, whether, for example, by one or moreseparate administrations, or by continuous infusion. A typical dailydosage is in the range from about 1 μg/kg to 100 mg/kg or more,depending on the factors mentioned above. For repeated administrationsover several days or longer, depending on the condition, the treatmentis sustained until a desired suppression of disease symptoms occurs.However, other dosage regimens may be useful. Unit doses can be in therange, for instance of about 5 mg to 500 mg, such as 50 mg, 100 mg, 150mg, 200 mg, 250 mg and 300 mg. Specific dosages include 0.1 mg, 0.5 mg,1, mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6mg, 6.5 mg, 7.0 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12mg, 13, mg 14 mg, 15 mg, 16 mg, 7 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg,35 mg, 40 mg, 45 mg and 50 mg. The progress of therapy is monitored byconventional techniques and assays.

In some aspects, a compound of formula (I) can be administered to ahuman subject at an effective amount (or dose) of less than about 1μg/kg, for instance, about 0.35 to about 0.75 μg/kg or about 0.40 toabout 0.60 μg/kg. In some aspects, the dose of the compound is about0.35 μg/kg, or about 0.40 μg/kg, or about 0.45 μg/kg, or about 0.50μg/kg, or about 0.55 μg/kg, or about 0.60 μg/kg, or about 0.65 μg/kg, orabout 0.70 μg/kg, or about 0.75 μg/kg, or about 0.80 μg/kg, or about0.85 μg/kg, or about 0.90 μg/kg, or about 0.95 μg/kg or about 1 μg/kg.In various aspects, the absolute dose of a compound is about 2μg/subject to about 45 μg/subject, or about 5 to about 40, or about 10to about 30, or about 15 to about 25 μg/subject. In some aspects, theabsolute dose of a compound is about 20 μg, or about 30 μg, or about 40μg.

In various aspects, the dose of a compound of formula (I) may bedetermined by the human subject's body weight. For example, an absolutedose of a compound of about 2 μg for a pediatric human subject of about0 to about 5 kg (e.g. about 0, or about 1, or about 2, or about 3, orabout 4, or about 5 kg); or about 3 μg for a pediatric human subject ofabout 6 to about 8 kg (e.g. about 6, or about 7, or about 8 kg), orabout 5 μg for a pediatric human subject of about 9 to about 13 kg (e.g.9, or about 10, or about 11, or about 12, or about 13 kg); or about 8 μgfor a pediatric human subject of about 14 to about 20 kg (e.g. about 14,or about 16, or about 18, or about 20 kg), or about 12 μg for apediatric human subject of about 21 to about 30 kg (e.g. about 21, orabout 23, or about 25, or about 27, or about 30 kg), or about 13 μg fora pediatric human subject of about 31 to about 33 kg (e.g. about 31, orabout 32, or about 33 kg), or about 20 μg for an adult human subject ofabout 34 to about 50 kg (e.g. about 34, or about 36, or about 38, orabout 40, or about 42, or about 44, or about 46, or about 48, or about50 kg), or about 30 μg for an adult human subject of about 51 to about75 kg (e.g. about 51, or about 55, or about 60, or about 65, or about70, or about 75 kg), or about 45 μg for an adult human subject ofgreater than about 114 kg (e.g. about 114, or about 120, or about 130,or about 140, or about 150 kg).

In one aspect, the compound formula (I) may be administered to a mammal(e.g., a human) at a dose of about 7.5 mg/kg.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

As used herein, the terms “fertility” or “fertile” refer to the abilityto produce offspring.

As used herein, the terms “infertility” of “infertile” refer to areduced ability or inability to produce offspring. The term “reversibleinfertility” as used herein relates to the induction of infertility in asubject which is then reversed so that the subject is fertile. Thecompounds disclosed herein produce reversible infertility in malesubjects. While the compounds are administered the subjects becomeinfertile and are unable to produce offspring. After cessation ofadministration of the disclosed compounds the subjects are no longerinfertile and have the ability to produce offspring. In someembodiments, infertility is measured as less than 20 million sperm permilliliter, less than 19 million sperm per milliliter, less than 18million sperm per milliliter, less than 17 million sperm per milliliter,less than 16 million sperm per milliliter, less than 15 million spermper milliliter, less than 14 million sperm per milliliter, less than 13million sperm per milliliter, less than 12 million sperm per milliliter,less than 11 million sperm per milliliter, less than 10 million spermper milliliter, less than 9 million sperm per milliliter, less than 8million sperm per milliliter, less than 7 million sperm per milliliter,less than 6 million sperm per milliliter, less than 5 million sperm permilliliter, less than 4 million sperm per milliliter, less than 3million sperm per milliliter, less than 2 million sperm per milliliter,less than 1 million sperm per milliliter. In some embodiments,infertility is measured as motility less than 40%, 35%, 30%, 25%, 20%,15%, 10%, 5% 0%. In some embodiments, infertility is measured as lessthan 12% normal morphologic sperm, less than 11% normal morphologicsperm, less than 10% normal morphologic sperm, less than 9% normalmorphologic sperm, less than 8% normal morphologic sperm, less than 7%normal morphologic sperm, less than 6% normal morphologic sperm, lessthan 5% normal morphologic sperm, less than 4% normal morphologic sperm,less than 3% normal morphologic sperm, less than 2% normal morphologicsperm, or less than 1% normal morphologic sperm.

In one embodiment, infertility is achieved in less than 145 days, 140days, 135 days, 130 days, 125 days, 120 days, 115 days, 110 days, 105days, 100 days, 95 days, 90 days, 85 days, 80 days, 75 days, 70 days, 65days, 60 days, 55 days, 50 days, 45 days, 40 days, 35 days, 30 days, 29days, 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days,4 days, 3 days, 2 days, or 1 days after treatment. In one embodiment,infertility is achieved in less than 20 weeks, 19 weeks, 18 weeks, 17weeks, 16 weeks, 15 weeks, 14 weeks, 13 weeks, 12 weeks, 11 weeks, 10weeks, 9 weeks, 8 weeks, 7 weeks, 6 weeks, 5 weeks, 4 weeks, 3 weeks, 2weeks, or 1 weeks.

The term “contraceptive” as used here in refers a method, pharmaceuticalagent or compound or device used to prevent pregnancy.

The term “disease or condition associated with RAR alpha activity”refers to any condition that can be improved by administering a RARalpha specific antagonist. Examples of such diseases and conditionsinclude cancer, metabolic disease, eye diseases, acne, neurodegenerativediseases and renal diseases.

The term “disease or condition associated with RAR alpha activity” alsoincludes: aging, depression, hyperlipidemia, vascular trauma (e.g.,lowering serum triglycerides), ischemic injury (e.g., in dermal tissue)and rheumatoid arthritis. Additionally, the compounds of the inventionmay also be useful for reducing mucin secretion, to reduce theside-effects of chemotherapy or radiation therapy, as an antidote forretinoid intoxication, to inhibit viral (e.g., HIV, humancytomegalovirus) replication, or to antagonize the inhibitive effect ofATRA and rescue BMP2-induced osteoblastogenesis.

The term “cancer” refers to a group of diseases characterized byabnormal and uncontrolled cell proliferation starting at one site(primary site) with the potential to invade and to spread to otherssites (secondary sites, metastases) which differentiate cancer(malignant tumor) from benign tumor. Virtually all the organs can beaffected, leading to more than 100 types of cancer that can affecthumans. Cancers can result from many causes including geneticpredisposition, viral infection, exposure to ionizing radiation,exposure environmental pollutant, tobacco and or alcohol use, obesity,poor diet, lack of physical activity or any combination thereof. As usedherein, “neoplasm” or “tumor” including grammatical variations thereof,means new and abnormal growth of tissue, which may be benign orcancerous. In a related aspect, the neoplasm is indicative of aneoplastic disease or disorder, including but not limited, to variouscancers. For example, such cancers can include prostate, pancreatic,biliary, colon, rectal, liver, kidney, lung, testicular, breast,ovarian, pancreatic, brain, and head and neck cancers, melanoma,sarcoma, multiple myeloma, leukemia, lymphoma, and the like.

Metabolic diseases are disorders that negatively alters the body'sprocessing and distribution of macronutrients such as proteins, fats,and carbohydrates. Metabolic diseases include obesity and diabetes.

Neurodegenerative diseases are a heterogeneous group of disorders thatare characterized by the progressive degeneration of the structure andfunction of the central nervous system or peripheral nervous system.Examples of neurodegenerative diseases include Alzheimer's disease andParkinson's disease.

Renal diseases are diseases that cause damage to the kidney. Examples ofrenal diseases include glomerulosclerosis and polycystic kidney disease.

The invention will now be illustrated by the following non-limitingExamples.

EXAMPLES General Scheme for Preparing Compounds of Formula (I)

Example 1. Synthesis of Sodium4-(5-(2,2-dimethyl-4-(p-tolyl)-2H-chromen-6-yl)-1H-pyrrol-2-yl)benzoate

a. Preparation of 6-bromo-2,2-dimethyl-4-(p-tolyl)-2H-chromene

To a solution of ketone (8.00 g, 31.4 mmol, 1 eq.) in THE (20 mL),p-tolylmagnesium bromide (100 mL, 1 M in THF, 3.2 eq.) was added slowlyover 15 minutes at 0° C. The reaction mixture was slowly warmed to roomtemperature and stirred for 36 h. Then the reaction was quenched withsaturated NH₄Cl solution at 0° C. and extracted with EtOAc (40×3 mL) Theorganic layers were collected, washed with brine, dried over Na₂SO₄, andevaporated to obtain a semisolid crude product. It was then dissolved inanhydrous MeOH (60 mL) and PPTS (1.60 g, 6.37 mmol, 0.2 eq.) was addedto the reaction mixture and refluxed for 4 h. Then the solvent wasevaporated under reduced pressure and the reaction mixture was dissolvedin EtOAc:water (30 mL: 30 mL) and extracted with EtOAc (30×3 mL).Organic layer was washed with brine, dried over Na₂SO₄, and evaporatedto dryness. Dried residue was purified by flash column chromatography(SiO₂, 100% hexanes to 5% EtOAc in hexanes) to obtain titled compound(6.89 g, 67%). ¹H NMR (400 MHz, CD₃OD) δ 7.31-7.27 (m, 5H), 7.19 (d,J=2.3 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 5.67 (s, 1H), 2.45 (s, 3H), 1.53(s, 6H).

b. Preparation of 2,2-dimethyl-4-(p-tolyl)-2H-chromene-6-carbaldehyde

6-Bromochromene (2.43 g, 7.38 mmol) was dissolved in anhydrous THF (13mL) and the reaction mixture was cooled to −78° C. To this, was addedn-BuLi (4.20 mL, 6.64 mmol) and the reaction mixture was stirred for 30minutes at −78° C. DMF (0.92 mL, 11.80 mmol) was then added to thereaction mixture at −78° C. and the reaction was stirred for additional45 minutes at the same temperature. After the completion of the reactionas monitored by TLC, the reaction mixture was warmed to 0° C. andquenched with saturated NH₄Cl solution. The aqueous layer was extractedtwice with ethyl acetate. The combined organic layer was dried overNa₂SO₄ and the solvent was evaporated. The crude reaction mixture waspurified using flash column chromatography to obtain the titled compoundas white solid (1.1 g, 54%). ¹H NMR (400 MHz, CDCl₃) δ 9.79 (s, 1H),7.73 (dd, J=8.3, 1.9 Hz, 1H), 7.58 (d, J=2.1 Hz, 1H), 7.31-7.23 (m, 4H),7.00 (d, J=8.3 Hz, 1H), 5.68 (s, 1H), 2.44 (s, 3H), 1.55 (s, 6H). ¹³CNMR (100 MHz, CDCl₃) δ 190.9, 159.3, 138.1, 134.7, 133.9, 131.5, 129.9,129.5, 129.4, 128.6, 127.9, 122.6, 117.6, 77.7, 28.3, 21.4.

c. Preparation of1-(2,2-dimethyl-4-(p-tolyl)-2H-chromen-6-yl)prop-2-en-1-ol

The aldehyde (1 g, 3.59 mmol) was dissolved in anhydrous THE (36 mL) andthe reaction mixture was cooled to −78° C. To this was addedvinylmagnesium bromide (4 mL, 3.59 mmol) and the reaction mixture wasallowed to warm up slowly to −10° C. over 1 h. The reaction was quenchedafter complete conversion of starting material as monitored by TLC withsaturated solution of ammonium chloride. The aqueous layer was extractedwith ethyl acetate. The combined organic layer was dried over Na₂SO₄ andthe solvent was evaporated. The crude reaction mixture was purified byusing flash column chromatography to yield the allylic alcohol productas yellow viscous oil (743 mg, 67%). ¹H NMR (400 MHz, CDCl₃) δ 7.27 (dd,J=12.7, 4.5 Hz, 4H), 7.19 (dd, J=8.3, 2.2 Hz, 1H), 7.07 (d, J=2.1 Hz,1H), 6.90 (d, J=8.3 Hz, 1H), 6.03 (ddd, J=16.6, 10.3, 5.8 Hz, 1H), 5.63(s, 1H), 5.30 (dt, J=17.2, 1.5 Hz, 1H), 5.17 (dt, J=10.5, 1.4 Hz, 1H),5.08 (dd, J=5.7, 3.2 Hz, 1H), 2.44 (s, 3H), 1.85 (d, J=3.5 Hz, 1H), 1.51(d, J=2.2 Hz, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 153.2, 140.4, 137.6,135.4, 134.9, 134.7, 136.9, 133.4, 130.1, 128.0, 127.3, 124.1, 122.5,117.9, 114.9, 76.0, 75.2, 27.8, 27.7, 21.4.

d. Preparation of1-(2,2-dimethyl-4-(p-tolyl)-2H-chromen-6-yl)prop-2-en-1-one

To a stirring solution of chromene-allylic alcohol (70 mg, 0.23 mmol) inanhydrous dichloromethane (2 mL) was added 8 equivalent of manganesedioxide (160 mg, 1.8 mmol, activated by heating in the oven for 1-2 h).The reaction was stirred at room temperature for 3 hours. To this wasadded another batch of manganese dioxide (160 mg, 1.8 mmol) and theresulting reaction mixture was stirred for an additional 2 hours afterwhich TLC showed complete consumption of starting material. The reactionmixture was filtered through Celite® and the solvent was evaporated. Thecrude product was purified using flash column chromatography to obtainthe vinyl ketone as a colorless viscous liquid (51 mg, 73%). ¹H NMR (400MHz, CDCl₃) δ 7.89 (dd, J=8.5, 2.1 Hz, 1H), 7.80-7.76 (m, 1H), 7.33-7.25(m, 4H), 7.10 (dd, J=17.0, 10.5 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.43(dd, J=17.0, 1.9 Hz, 1H), 5.86 (dd, J=10.5, 1.8 Hz, 1H), 5.71 (s, 1H),2.47 (s, 3H), 1.58 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 189.1, 158.0,137.8, 134.6, 134.0, 132.0, 130.5, 130.1, 129.3, 129.1, 129.0, 128.4,126.7, 122.1, 77.2, 27.9, 21.2.

e. Preparation of methyl4-(4-(2,2-dimethyl-4-(p-tolyl)-2H-chromen-6-yl)-4-oxobutanoyl)benzoate

To a stirring solution of1-(2,2-dimethyl-4-(p-tolyl)chroman-6-yl)prop-2-en-1-one (392 mg, 1.28mmol) in DMF (4 mL) was added3-benzyl-5-(2-hydroxyethyl)-4-methylthiazol-3-ium Chloride (69.1 mg,0.26 mmol) followed by methyl 4-formylbenzoate (210 mg, 1.28 mmol) andtriethylamine (0.2 ml, 1.54 mmol). The reaction mixture was degassed for5-10 minutes and heated to 80° C. Upon completion as monitored by TLC,the reaction mixture was cooled to room temperature and diluted withethyl acetate and water. The aqueous layer was extracted twice withethyl acetate and the combined organic layer was dried (Na₂SO4) andevaporated. The crude product was purified using flash columnchromatography. ¹H NMR (400 MHz, CDCl₃) δ 8.16 (d, J=8.1 Hz, 2H), 8.09(d, J=8.1 Hz, 2H), 7.95-7.87 (m, 1H), 7.78 (d, J=2.2 Hz, 1H), 7.31-7.22(m, 4H), 6.96 (d, J=8.4 Hz, 1H), 5.68 (s, 1H), 3.98 (s, 3H), 3.44-3.38(m, 2H), 3.38-3.33 (m, 2H), 2.42 (s, 3H), 1.55 (s, 6H). ¹³C NMR (101MHz, CDCl₃) δ 198.5, 196.8, 166.2, 158.1, 140.1, 137.8, 134.6, 134.1,133.8, 129.9, 129.8, 129.6, 129.3, 129.0, 128.4, 128.0, 126.1, 122.0,116.8, 77.1, 52.4, 32.8, 32.1, 27.9, 21.2.

f. Preparation of methyl4-(5-(2,2-dimethyl-4-(p-tolyl)-2H-chromen-6-yl)-1H-pyrrol-2-yl)benzoate

Methyl4-(4-(2,2-dimethyl-4-(p-tolyl)-2H-chromen-6-yl)-4-oxobutanoyl)benzoate(440 mg, 0.939 mmol) was dissolved in glacial AcOH (16 mL) and to thiswas added ammonium acetate (362 mg, 4.70 mmol). The reaction mixture wasthen refluxed at 110° C. for 18 h. Upon completion as monitored by TLCthe solvent was removed and crude product was dissolved in EtOAc (50 mL)and washed with saturated sodium bicarbonate solution. The combinedorganic layer was dried (Na₂SO₄), evaporated and purified using flashcolumn chromatography. ¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 1H), 8.00 (d,J=8.1 Hz, 2H), 7.50 (d, J=7.7 Hz, 2H), 7.36 (d, J=7.6 Hz, 1H), 7.29 (d,J=7.8 Hz, 3H), 7.23 (d, J=7.6 Hz, 3H), 6.93 (d, J=8.3 Hz, 1H), 6.65 (s,1H), 6.38 (s, 1H), 5.66 (s, 1H), 3.90 (s, 3H), 2.42 (s, 3H), 1.51 (s,6H). ¹³C NMR (101 MHz, CDCl₃) δ 130.3, 129.5, 129.2, 128.5, 127.0,125.2, 125.0, 122.8, 121.6, 117.4, 109.7, 107.5, 76.1, 52.0, 27.6, 21.2.

g. Preparation of4-(5-(2,2-dimethyl-4-(p-tolyl)-2H-chromen-6-yl)-1H-pyrrol-2-yl)benzoicAcid

To a stirring solution of pyrrole ester (309 mg, 0.687 mmol) in ethanol(26 ml) was added NaOH solution (20% wt/wt, 3.44 mmol) and the reactionmixture was stirred for 48 h at room temperature till completedisappearance of starting material as monitored by TLC. The solvent wasthen evaporated and the reaction was acidified using 6N HCl to pH 6-7.The aqueous layer was extracted with ethyl acetate (2×50 ml)) and thenwith dichloromethane (2×50 ml). The combined organic layer was dried(Na₂SO₄) and the solvent was evaporated. The crude product was purifiedusing flash column chromatography to yield the titled compound as ayellow solid (230 mg, 76%). ¹H NMR (400 MHz, CD₃OD) δ 7.96 (d, J=8.2 Hz,2H), 7.68 (d, J=8.2 Hz, 2H), 7.51 (dd, J=8.3, 2.2 Hz, 1H), 7.35-7.16 (m,5H), 6.88 (d, J=8.4 Hz, 1H), 6.63 (d, J=3.6 Hz, 1H), 6.25 (d, J=3.7 Hz,1H), 5.68 (s, 1H), 2.40 (s, 3H), 1.48 (s, 6H). ¹³C NMR (100 MHz, CD₃OD)δ 169.9, 153.7, 138.9, 138.8, 136.8, 136.6, 136.1, 132.9, 131.3, 130.3,130.2, 129.7, 128.0, 127.2, 126.6, 124.1, 123.9, 123.1, 118.1, 110.5,108.0, 76.9, 27.7, 21.3.

h. Preparation of Sodium4-(5-(2,2-dimethyl-4-(p-tolyl)-2H-chromen-6-yl)-1H-pyrrol-2-yl)benzoate

To a stirring solution of acid dissolved in methanol was added 1 Maqueous NaOH solution dropwise and the resulting mixture was stirred atrt for 30 mins. The solvent was evaporated and the crude reactionmixture was co-evaporated with toluene (3 times) to remove any traces ofwater. The solid was further washed with 5% aqueous acetone to removeany inorganic impurities and thereafter evaporated to dryness to yieldthe sodium salt as a yellow solid (quantitative yield). ¹H NMR (400 MHz,CD₃OD) δ 7.91 (d, J=8.1 Hz, 2H), 7.59 (d, J=8.2 Hz, 2H), 7.51 (dd,J=8.4, 2.2 Hz, 1H), 7.29 (d, J=7.6 Hz, 5H), 6.87 (d, J=8.4 Hz, 1H), 6.53(d, J=3.6 Hz, 1H), 6.22 (d, J=3.6 Hz, 1H), 5.69 (s, 1H), 2.42 (s, 3H),1.49 (s, 6H). 13C NMR (100 MHz, CD₃OD) δ 175.6, 153.4, 138.8, 136.8,136.3, 136.2, 135.8, 135.6, 133.8, 130.8 (2C), 130.2, 130.1 (2C), 129.7(2C), 127.5, 126.4, 123.9, 123.9, 123.0, 118.1, 109.0, 108.9, 107.6,76.9, 27.7 (2C), 21.3.

Example 2. Alternative Synthesis of Representative Compounds of Formula(I)

a. Preparation of tert-Butyl2-(4-(methoxycarbonyl)phenyl)-1H-pyrrole-1-carboxylate

The aryl halide (17.00 g, 79.05 mmol, 1 eq.) and 1-boc-pyrrole-5-boronicacid (20.00 g, 94.78 mmol, L2 eq.), were combined in a round bottomflask followed by addition of THF (190 mL) and aqueous solution of K₃PO₄(0.5 M, 380 mL, 2.4 eq.). Nitrogen gas was bubbled through the reactionmixture for 15 minutes followed by addition of XPhos Pd G2 (1.50 g, 1.91mmol, 0.024 equiv.). Then the flask was placed in a preheated oil bathat 45° C. and stirred for 5 hours. After the reaction was complete,brine was added and the mixture was extracted with EtOAc (50 mL×3) anddried with MgSO₄. The solvent was evaporated to dryness. The residue waspurified by flash column chromatography (SiO₂, 100% hexanes to 20% EtOAcin hexanes) to obtain the coupled product as a white solid (22.142 g,93%). ¹H NMR (400 MHz, CDCl₃) δ 8.06-7.98 (m, 2H), 7.45-7.35 (m, 3H),6.29-6.21 (n, 2H), 3.93 (s, 3H), 1.37 (s, 9H) ¹³C NMR (100 MHz, CDCl₃) δ167.1, 149.3, 139.1, 134.1, 129.1, 128.7, 123.6, 115.6, 111.0, 84.2,52.2, 27.8 This compound is also commercially available.

b. Preparation of Methyl 4-(1H-Pyrrol-2-yl)benzoate

The product from step a (18.13 g, 60.16 mmol, 1 eq.) was dissolved inTHF (60 mL) and NaOMe (80 mL, 25 wt,% in MeOH, 6 eq.) was added. Themixture was stirred for 5 minutes and quenched with saturated NH₄Clsolution. The resulting mixture was extracted with dichloromethane (50mL×3) and the organic phase was dried with MgSO₄ and evaporated todryness to provide the deprotected product as a white solid (11.615 g,96%). ¹H NMR (400 MHz, CDCl₃) δ 8.62 (s, 1H), 8.09-8.01 (m, 2H),7.59-7.51 (m, 2H), 6.95 (td, J=2.7, 1.4 Hz, 1H), 6.69 (ddd, J=3.8, 2.7,1.4 Hz, 1H), 6.36 (dt, J=3.7, 2.6 Hz, 1H), 3.94 (s, 3H). ¹³C NMR (100MHz, CDCl₃) δ 166.9, 136.8, 131.0, 130.4, 127.3, 1231, 120.3, 110.7,108.0, 52.1.

c. Preparation of Methyl4-(5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrol-2-yl)benzoate

The product from step b (12.00 g, 59.63 mmol, 1 eq.), B₂Pin₂ (8.304 g,32.7 mmol, 0.55 eq.) [Ir(COD)OMe] (0.60 g, 0.91 mmol, 0.015 eq.), and4,4′-dtbpy (0.484 g, 1.80 mmol, 0.03 eq) were combined in a round bottomflask, evacuated under vacuum, and purged with nitrogen. This processwas repeated three times followed by mixing with hexanes (120 mL). Thesuspension was refluxed under nitrogen for 6 hours. After 6 hours, thereaction mixture was solubilized in DCM and a silica gel slurry wasprepared for flash chromatography (SiO, 100% hexanes to 20% EtOAc inhexanes) to obtain the pyrrole boronate product as an off-white solid(16.71 g, 86%). %). ¹H NMR (400 MHz, CDCl₃) δ 8.99 (s, 1H), 8.07-8.00(m, 2H), 7.63-7.56 (m, 2H), 6.89 (dd, J=3.7, 2.4 Hz, 1H), 6.69 (dd,J=3.7, 2.5 Hz, 1H), 3.92 (s, 3H), 1.34 (s, 12H). ¹³C NMR (101 MHz,CDCl₃) δ 167.0, 136.4, 135.6, 130.5, 128.2, 124.0, 122.1, 109.3, 84.1,52.2, 24.9.

d. Preparation of 6-Bromo-2,2-dimethyl-4-(p-tolyl)-2H-chromene

To a solution of bromochromone (8.00 g, 31.4 mmol, 1 eq.) in THE (20mL), p-tolylmagnesium bromide (100 mL, 1 M in THF, 3.2 eq.) was addedslowly over 15 minutes at 0° C. The reaction mixture was slowly warmedto room temperature and stirred for 36 hours. The reaction was quenchedwith saturated NH₄Cl solution at 0° C. and extracted with EtOAc (40×3mL). The organic layers were collected, washed with brine, dried overMgSO₄, and evaporated to obtain a semisolid crude product. The semisolidcrude product was dissolved in anhydrous MeOH (60 mL) and PPTS (1.60 g,6.37 mmol, 0.2 eq.) was added. The resulting mixture was allowed toreflux for 4 hours. The solvent was evaporated under reduced pressureand the resulting material was dissolved in EtOAc:water (30 mL:30 mL)and extracted with EtOAc (30×3 mL). The combined organic layers werewashed with brine, dried over MgSO₄, and evaporated to dryness. Theresidue was purified by flash column chromatography (SiO₂, 100% hexanesto 5% EtOAc in hexanes) to provide the bromochromene product (6.89 g,67%) as a colorless liquid that turned solid upon freezing. ¹H NMR (400MHz, CD₃OD) δ 7.31-7.27 (m, 5H), 7.19 (d, J=2.3 Hz, 1H), 6.82 (d, J=8.5Hz, 1H), 5.67 (s, 1H), 2.45 (s, 3H), 1.53 (s, 6H). ¹³C NMR (100 MHz,CD₃OD) δ 152.5, 137.8, 134.8, 133.9, 131.8, 129.8, 129.3, 128.5, 128.2,124.5, 118.7, 112.8, 76.2, 27.6, 21.3.

e. Preparation of methyl4-(5-(2,2-dimethyl-4-(p-tolyl)-2H-chromen-6-yl)-1H-pyrrol-2-yl)benzoate

The bromochromene from step d (580 mg, 1.76 mmol, 1 eq.) and the pyrroleboronate from step c (630 mug, 1.93 mmol, 1, eq.), were combined in avial and dissolved into THF (3.5 mL) and an aqueous solution of K₃PO₄(0.5 M, 7 mL, 2.0 eq.) was added. Nitrogen gas was bubbled through thereaction mixture for 15 minutes followed by addition of XPhos Pd G2(0.035 g, 0.04 mmol, 0.025 eq.). The mixture was placed in a preheatedoil bath at 45° C. and stirred for 3 hours, After the reaction wascomplete, brine was added and the resulting mixture was extracted withEtOAc (50 ml×3). The combined organics were dried over MgSO₄ andevaporated to dryness. The residue was purified by flash columnchromatography (SiO₂, 100% hexanes to 20% EtOAc in hexanes) to providethe chromene ester product as a bright yellow solid (681 g, 86%).

f. Preparation of4-(5-(2,2-dimethyl-4-(p-tolyl)-2H-chromen-6-yl)-1H-pyrrol-2-yl)benzoicAcid

To a solution of chromene ester product (600 ng, 1.33 mmol, 1 eq.) inTHF (10 mL) and MeOH (10 mL), was added LiOH (280 mg, 6.67 mmol, 5 eq.)dissolved in water (10 mL) and the resulting mixture was stirred for 20hours at room temperature. The organic layer was evaporated underreduced pressure and the aqueous suspension was acidified with 2N HCl toreach pH 1.0. Then mixture was extracted with EtOAc (10 mL×3), washedwith brine, and dried with MgSO₄. The extract was purified by flashcolumn chromatography (SiO₂, 100% hexanes to 50% EtOAc and 2% HCOOH inhexanes) to provide the acid (526 mg, 91%) as a yellow solid.

Example 3 Sodium4-(5-(2,2-dimethyl-4-(p-tolyl)-2H-chromen-6-yl)-1H-pyrrol-2-yl)-2-fluorobenzoate

a. Preparation of methyl 2-fluoro-4-(1H-pyrrol-2-yl)benzoate

To a stirring solution of 1H-pyrrole (230 mg, 238 μL, 4 Eq, 3.43 mmol)in N,N-dimethylacetamide (3 mL, 0.3 molar) was added palladium(II)acetate (9.63 mg, 0.05 Eq, 42.9 μmol), potassium acetate (168 mg, 2 Eq,1.72 mmol) and methyl 4-bromo-2-fluorobenzoate (200 mg, 1 Eq, 858 μmol).The solution was degassed using nitrogen for 15 minutes. The resultingsolution was heated in a sealed tube at 150° C. for 36 hours. Thereaction mixture was purified directly using flash column chromatographyto give the titled compound (150 mg, 80%). ¹H NMR (400 MHz, CDCl₃) δ8.59 (s, 1H), 7.93 (t, J=8.0 Hz, 1H), 7.28 (dd, J=8.3, 1.7 Hz, 1H), 7.20(dd, J=12.2, 1.8 Hz, 1H), 6.94 (td, J=2.7, 1.3 Hz, 1H), 6.67 (dq, J=3.8,1.6 Hz, 1H), 6.34 (q, J=2.8 Hz, 1H), 3.93 (s, 3H).

b. Preparation of methyl2-fluoro-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrol-2-yl)benzoate

To a solution of methyl 2-fluoro-4-(1H-pyrrol-2-yl)benzoate (141 mg, 1Eq, 0.643 mmol) in anhydrous n-hexane (5.88 mL, 0.170 molar) were added4,4′-di-tert-butyl-2,2′-bipyridine (5.18 mg, 0.030 Eq, 19.3 μmol),bis(pinacolato)diboron (163 mg, 1 Eq, 643 μmol) and(1,5-Cyclooctadiene)(methoxy)iridium (I) dimer (6.39 mg, 0.015 Eq, 9.64μmol). The resulting mixture (not homogeneous) was heated to reflux andstirred for 1 and half hour (Within 1 h of heating the reaction colorchanged to dark brown and reaction mixture becomes homogeneous). Thecrude mixture was then evaporated and directly purified using flashcolumn chromatography to provide the titled compound (142 mg, 64%). ¹HNMR (400 MHz, CDCl₃) δ 9.13 (s, 1H), 7.96 (t, J=7.9 Hz, 1H), 7.37 (dd,J=8.3, 1.7 Hz, 1H), 7.30 (dd, J=12.3, 1.6 Hz, 1H), 6.90 (dd, J=3.7, 2.3Hz, 1H), 6.71 (dd, J=3.7, 2.5 Hz, 1H), 3.95 (s, 3H), 1.36 (s, 12H).

c. Preparation of 6-Iodo-2,2-dimethylchroman-4-one

To a solution of 1-(2-hydroxy-5-iodophenyl)ethan-1-one (2.00 g, 1 Eq,7.63 mmol) in methanol (40.0 mL, 0.19 molar, 1.0 Eq, 7.6 mmol) wereadded pyrrolidine (847 mg, 0.98 mL, 1.56 Eq, 11.9 mmol) and acetone (678mg, 0.86 mL, 1.53 Eq, 11.7 mmol). The reaction mixture was left stirringovernight. TLC showed complete consumption of starting material, MeOHwas evaporated and the crude mixture was washed with 1N HCl (aqueous),extracted with EtOAc. The crude reaction mixture was dried over Na₂SO₄and evaporated. The resulting residue was purified on flash columnchromatography (silica gel, hexanes/ethyl acetate, 100:00 to 70:30) togive the titled compound (1.86 g, 81%, brown oil). ¹H NMR (400 MHz,CDCl₃) δ 8.12 (d, J=2.3 Hz, 1H), 7.68 (dd, J=8.7, 2.3 Hz, 1H), 6.69 (d,J=8.7 Hz, 1H), 2.69 (s, 2H), 1.43 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ191.1, 159.6, 144.4, 135.2, 122.1, 120.9, 82.9, 79.7, 48.5, 26.6.

d. Preparation of 6-iodo-2,2-dimethyl-4-(p-tolyl)-2H-chromene

The title compound was prepared compound (55% off-white solid) followingthe procedure described for its bromo analog. ¹H NMR (400 MHz, CDCl₃)7.47 (dd, J=8.5, 2.2 Hz, 1H), 7.34 (d, J=2.2 Hz, 1H), 7.26 (s, 4H), 6.70(d, J=8.5 Hz, 1H), 5.64 (s, 1H), 2.45 (s, 3H), 1.52 (s, 6H).

e. Preparation of methyl4-(5-(2,2-dimethyl-4-(p-tolyl)-2H-chromen-6-yl)-1H-pyrrol-2-yl)-2-fluorobenzoate

To a mixture of 6-iodo-2,2-dimethyl-4-(p-tolyl)-2H-chromene (154 mg, 1Eq, 0.408 mmol) and methyl2-fluoro-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrol-2-yl)benzoate(141 mg, 1.00 Eq, 0.408 mmol) in 1,4-dioxane (12.36 mL, 0.033 molar) andwater (1.24 mL, 0.33 molar) were added sodium carbonate (303 mg, 7 Eq,2.86 mmol), diacetoxypalladium (14.7 mg, 0.160 Eq, 0.0653 mmol) anddicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphane (97.3mg, 0.500 Eq, 0.204 mmol). The resulting solution was degassed for 15minutes using N₂ gas. The reaction mixture was then refluxed at 100° C.for 16 h. The crude reaction mixture was evaporated to dryness andpurified via flash column chromatography to afford the titled compound(149 mg, 78%). ¹H NMR (400 MHz, CDCl₃) δ 8.75 (s, 1H), 7.81 (t, J=8.0Hz, 1H), 7.30 (dd, J=8.4, 2.2 Hz, 1H), 7.23-7.10 (m, 7H), 6.84 (d, J=8.3Hz, 1H), 6.57 (t, J=3.2 Hz, 1H), 6.33-6.25 (m, 1H), 5.57 (s, 1H), 3.83(s, 3H), 2.33 (s, 3H), 1.43 (s, 6H).

f. Preparation of sodium4-(5-(2,2-dimethyl-4-(p-tolyl)-2H-chromen-6-yl)-1H-pyrrol-2-yl)-2-fluorobenzoate

To a stirring solution of pyrrole ester (97 mg, 0.21 mmol) in ethanol(2.0 mL) was added aqueous sodium hydroxide solution (5 M, 1 mmol) andthe reaction mixture was stirred for 48 h at room temperature tillcomplete disappearance of starting material as monitored by TLC. Thesolvent was then evaporated, and the reaction was acidified using 6N HClto pH 6-7. The aqueous layer was extracted with ethyl acetate (2×10 ml))and then with dichloromethane (2×10 mL). The combined organic layer wasdried over sodium sulfate and the solvent was evaporated to give acid(47 mg, 50%). To a stirring solution of acid (20 mg, 44 mmol) dissolvedin anhydrous MeOH (0.44 mL) was added sodium hydroxide (1 M, 40 mL) andthe resulting mixture was stirred at room temperature for 30 minutes.The solvent was evaporated and the crude reaction mixture wasco-evaporated with toluene (3 times) to remove any traces of water. Thecrude solid was purified using reverse phase column chromatography togive the titled compound (quantitative yield). ¹H NMR (400 MHz, MeOD) δ7.64 (t, J=8.0 Hz, 1H), 7.49 (dd, J=8.3, 2.2 Hz, 1H), 7.38-7.32 (m, 1H),7.28 (d, J=12.4 Hz, 5H), 6.86 (d, J=8.4 Hz, 1H), 6.53 (d, J=3.6 Hz, 1H),6.21 (d, J=3.6 Hz, 1H), 5.68 (s, 1H), 2.40 (s, 3H), 1.48 (s, 6H).

Example 4 Sodium4-(5-(2,2-dimethyl-4-(p-tolyl)-2H-chromen-6-yl)-1H-pyrrol-2-yl)-2,6-difluorobenzoate

a. Preparation of methyl 2,6-difluoro-4-(1H-pyrrol-2-yl)benzoate

To a mixture of methyl 4-bromo-2,6-difluorobenzoate (300.00 mg, 1 Eq,1.1951 mmol) and2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (576.77 mg,2.5 Eq, 2.9877 mmol) in 1,4-dioxane (36.2 mL, 0.033 molar) and water(3.62 mL, 0.330 molar) were added sodium carbonate (886.66 mg, 7 Eq,8.37 mmol), diacetoxypalladium (42.93 mg, 0.16 Eq, 191.21 μmol) andXphos(dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphane)(284.9 mg, 0.5 Eq, 597.5 μmol). The resulting solution was degassed for15 minutes using N₂ gas. The reaction mixture was then refluxed at 100°C. for 16 h. The crude reaction mixture was evaporated to dryness andpurified via flash column chromatography to yield the titled compound(181 mg, 64%) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.93 (s, 1H),7.10-7.01 (m, 2H), 6.89 (td, J=2.8, 1.4 Hz, 1H), 6.61 (ddd, J=3.9, 2.6,1.4 Hz, 1H), 6.26 (dt, J=3.7, 2.5 Hz, 1H), 3.90 (s, 3H).

b. Preparation of methyl2,6-difluoro-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrol-2-yl)benzoate

The titled compound (234 mg, 60%) was prepared following the proceduredescribed for its mono-flouro analog. ¹H NMR (400 MHz, CDCl₃) δ 9.06 (s,1H), 7.12-7.05 (m, 2H), 6.86 (dd, J=3.7, 2.3 Hz, 1H), 6.66 (dd, J=3.7,2.5 Hz, 1H), 3.94 (s, 3H), 1.33 (s, 12H).

c. Preparation of methyl4-(5-(2,2-dimethyl-4-(p-tolyl)-2H-chromen-6-yl)-1H-pyrrol-2-yl)-2,6-difluorobenzoate

The titled compound was prepared using a procedure similar to thatdescribed in Example 3, sub-part e (33 mg, 80%). ¹H NMR (400 MHz, CDCl₃)δ 8.59 (s, 1H), 7.41-7.34 (m, 1H), 7.27 (dt, J=13.4, 6.8 Hz, 5H), 7.01(d, J=10.1 Hz, 2H), 6.95 (d, J=8.3 Hz, 1H), 6.65 (t, J=3.2 Hz, 1H), 6.40(d, J=3.2 Hz, 1H), 5.68 (s, 1H), 3.94 (s, 3H), 2.44 (s, 3H), 1.53 (s,6H).

d. Preparation of sodium4-(5-(2,2-dimethyl-4-(p-tolyl)-2H-chromen-6-yl)-1H-pyrrol-2-yl)-2,6-difluorobenzoate

The titled compound was prepared using a procedure similar to thatdescribed in Example 3, sub-part f (68 mg, 69%). ¹H NMR (400 MHz, MeOD)δ 7.49 (dd, J=8.4, 2.2 Hz, 1H), 7.32-7.23 (m, 5H), 7.17 (d, J=8.6 Hz,2H), 6.87 (d, J=8.3 Hz, 1H), 6.53 (d, J=3.7 Hz, 1H), 6.21 (d, J=3.7 Hz,1H), 5.68 (s, 1H), 2.40 (s, 3H), 1.48 (s, 6H).

Example 5. Metabolic Stability Assays

The metabolic stability of the compound of Example 1 was evaluated usingstandard assay protocols. Results are provided in the following tables.

Metabolic Stability of Test Compounds in Male Mouse Liver Microsomes

Remaining Percentage (%) @ 60 min Compound With NADPH Without NADPHVerapamil 2.68 104.75 Example 1 86.20 94.70 Verapamil 2.68 104.75Example 1 86.20 94.70

Metabolic Stability of Test Compounds in Pooled Human Liver Microsomes(a)

CL_(int) Scaled-up CL_(int) Compound Species T_(1/2) (min) (μL/min/mgprotein) (mL/min/Kg) Verapamil Human 15.39 90.08 112.97 Example 1 Human569.64 2.43 3.05

Metabolic Stability of Test Compounds in Pooled Human Liver Microsomes(b)

Com- Assay Remaining Percentage (%) pound Species Format 0 min 15 min 30min 45 min 60 min Vera- Human With 100.00  32.16  15.37  9.09   6.42pamil NADPH Without 100.00 105.07  94.01 91.24  94.01 NADPH Exam- HumanWith 100.00  97.20 104.60 95.66  92.01 ple NADPH 1 Without 100.00 104.88 89.43 98.37 101.63 NADPH

Example 6. Stability in Mouse and Human Hepatocytes

The metabolic stability of the compound of Example 1 was evaluated inmouse and human hepatocytes using standard assay protocols. Results areprovided in the following tables.

Metabolic Stability of Test Compounds in Human and Mouse Hepatocytes Invitro T_(1/2) In vitro Cl_(int) Scale-up Cl_(int) Compound Species (min)(μL/min/10⁶ cells) (mL/min/kg) Verapamil Human 25.90 53.51 136.15 Mouse16.13 85.94 1015.14 Example 1 Human 522.36 2.65 6.75 Mouse 289.56 4.7956.54

Metabolic Stability of Test Compounds in Human and Mouse HepatocytesRemaining Percentage (%) Assay 15 30 60 90 120 Compound Species Format 0min min min min min min Verapamil Human Hepatocytes 100.00 54.52 30.1513.32 7.23 3.73 Boiled 100.00 95.35 87.21 98.15 92.27 96.98 hepatocytesMouse Hepatocytes 100.00 43.64 18.29 6.52 1.90 0.61 Boiled 100.00 92.5891.42 89.53 86.22 87.28 hepatocytes Example 1 Human Hepatocytes 100.0090.54 100.06 94.23 84.66 84.71 Boiled 100.00 98.16 81.83 94.26 96.1489.50 hepatocytes Mouse Hepatocytes 100.00 90.50 90.43 87.11 76.03 74.05Boiled 100.00 92.45 99.92 103.79 113.92 107.73 hepatocytes

Example 7. Log D Calculations

The Log D's for the compound of Example 1 and progesterone weredetermined using standard assay protocols. Results are provided in thefollowing table.

Log D Results of Test Compounds in 1-Octanol/PBS pH 7.4 Compound LogDValue Progesterone 3.77 Example 1 3.40

Example 8. Solubility Measurements

The stabilities of the compound of Example 1 and progesterone in PBS atpH 7.4 were determined using standard assay protocols. Results areprovided in the following table.

Solubility Results of Test Compounds and Control Compound in PBS at pH7.4 Compound Solubility (μM) Progesterone 14.02 Example 1 78.57

Example 9. hERG Assay

The potential inhibitory effect on human Ether-á-go-go related gene(hERG) channel was evaluated using a manual patch-clamp system. A HEK293cell line stably transfected with hERG gene was employed. Dofetilide wasused as a positive control. The results are shown in the followingtables. From this data, the compound of Example 1 is ranked as a weakinhibitor on hERG channel.

Con- % of hERG Average % of centration inhibition inhibition Compound(μM) Cell 1 Cell 2 hERG SD Example 1 0.37 −0.16 −2.51 −1.33 1.66 1.113.73 3.62 3.68 0.08 3.33 6.99 16.45 11.72 6.69 10.00 19.54 20.16 19.850.44 30.00 35.90 43.18 39.54 5.14 Dofetilide 0.00185 3.38 8.52 5.95 3.640.00556 12.81 11.40 12.11 1.00 0.01667 53.60 53.10 53.35 0.35 0.0500082.47 85.29 83.88 2.00 0.15000 96.14 94.20 95.17 1.37

Test article hERG IC₅₀ [μM] Comment Compound of >30⁽¹⁾ 39.54% inhibition@ 30 Example 1 μM Dofetilide 0.016 ⁽²⁾ /

Example 10. Mini-Ames Assay

The compound of Example 1 was evaluated in a mini-Ames assay. Theresults were negative.

Example 11. HepG2 and Human Liver Fibroblast Assay

The compound of Example 1 was evaluated in a HepG2 cytotoxicity assay.The results were negative.

Example 12. Human Liver Fibroblast Assay

The compound of Example 1 was evaluated in a human liver fibroblastassay. The results were negative.

The data from Examples 5-12 is summarized below.

Summary of In Vitro Assays

-   -   Metabolic Stability (mouse): 86% after 1 hour    -   Metabolic Stability (human): 100% after 1 hour, t_(1/2)-570        minutes    -   Log D=3.5    -   Solubility: 2 mg/ml (saline)    -   hERG (negative, >30 μm)    -   Mini Ames (negative)    -   HepG2 cytotoxicity assay (negative)    -   Human lung fibroblast assay (negative)

Example 13. Transactivation Assay

A dose-response of agonist, 9-cis-retinoic acid (9-cis-RA) for RARα orall-trans-retinoic acid (ATRA) for RAR β and γ, and referenceantagonists BMS-189453 or BMS-189532 were included on every 384-wellplate. Control wells containing cells without added agonist defined thebackground signal values. An EC₅₀ concentration of agonist in DMSO (180nM 9-cis-RA for RARα, 8 nM ATRA for RAR β and γ) was added to controland compound wells using the Echo acoustic nanoliter dispenser (Labcyte,San Jose, Calif.). The compound of Example 1 and reference compounds inDMSO (final 0.4%) were added to plates in 8-point dose response intriplicate using the Echo. Cell suspension (30 μL) was added to eachwell and the assay plate was incubated overnight in a 5% CO₂ incubatorat 37° C. Luciferase detection reagent (15 μL) was then added and theplate was incubated at RT for 30 minutes. Luminescence was quantifiedusing an EnSpire plate reader (PerkinElmer, Waltham, Mass.). IC₅₀ valueswere determined by fitting dose response data using the four-parameterlogistic equation in GraphPad Prism 7.0. The resulting data is shownbelow.

IC₅₀RARα=6.8 nM

IC₅₀RARβ=>3700 nM

IC₅₀RARγ=>3700 nM

Example 14. Distribution Assay

30 CD-1 Mice were dosed orally with 10 mg/kg of the compound ofExample 1. At specified time points (5, 15, 30 min and 1, 2 4, 8, 16,24, 48 h) sets of 3 animals were bled and euthanized. Testes and brainwere then harvested. Resulting plasma and tissue were frozen at <−20° C.until analysis by LC/MS/MS. Peak levels in the plasma is about 2.1 μM at15 minutes post-dose, plateaus between 30 minutes and 8 hours at about1.5 μM and still remains detectable at 48 hours (12.9 nM). The resultingdata is shown in FIG. 1 .

Example 15. Effects on Male Fertility

Studies were performed on male mice to determine the effect of thecompound of Example 1 on male fertility. Mice were administered 10 mg/kgdaily for four weeks or 20 mg/kg daily for two weeks resulting ininfertility (FIG. 2 ). Following cessation of administration of thecompound fertility was restored.

Example 16. Mating Studies with Embryo Counts

Mating Studies with Embryo Counts were conducted as described by, Chung,S. S.; Wang, X.; Roberts, S. S.; Griffey, S. M.; Reczek, P. R.;Wolgemuth, D. J. Oral administration of a retinoic Acid receptorantagonist reversibly inhibits spermatogenesis in mice. Endocrinology2011, 152, 2492-2502. The data show that administration of the compoundof Example 1 to male mice at a dose of 10 mg/kg daily for four weeks or20 mg/kg daily for two weeks results in the induction of infertility(FIGS. 3 and 4 ). These experiments also demonstrated that the inductionof infertility was reversible. FIG. 5 shows that infertility induced inmale mice administered the compound of Example 1 at 10 mg/kg/day forfour weeks was reversed four to six weeks following cessation ofadministration of the compound. FIG. 6 shows that infertility induced inmale mice administered the compound of Example 1 at 20 mg/kg/day for twoweeks was reversed six weeks following cessation of administration ofthe compound.

Example 17. Representative Pharmaceutical Dosage Forms

The following illustrate representative pharmaceutical dosage forms,containing a compound of formula (I) (‘Compound X’), for therapeutic orprophylactic use in humans.

(i) Tablet 1 mg/tablet Compound X= 100.0 Lactose 77.5 Povidone 15.0Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesiumstearate 3.0 300.0

(ii) Tablet 2 mg/tablet Compound X= 20.0 Microcrystalline cellulose410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0500.0

(iii) Capsule mg/capsule Compound X= 10.0 Colloidal silicon dioxide 1.5Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0

(v) Injection 2 (10 mg/ml) mg/ml Compound X = (free acid form) 10.0Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethyleneglycol 400 200.0 1.0N Sodium hydroxide solution (pH adjustment to7.0-7.5) q.s. Water for injection q.s. ad 1 mL

(iv) Injection 1 (1 mg/ml) mg/ml Compound X = (free acid form) 1.0Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodiumchloride 4.5 1.0N Sodium hydroxide solution (pH adjustment to 7.0-7.5)q.s. Water for injection q.s. ad 1 mL

(vi) Aerosol mg/can Compound X= 20.0 Oleic acid 10.0Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0Dichlorotetrafluoroethane 5,000.0

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art.

Example 18. Safety Profile

Introduction and Objectives: Men are lacking contraceptive options thatmeet their needs and lifestyles. The compound of Example 1 acts as aretinoic acid receptor (RAR)-alpha antagonist thus inhibiting bothspermatogenesis and spermiogenesis. The compound of Example 1 hasdemonstrated a 99% contraceptive efficacy and full reversibility in miceat 10 mg/kg, and sufficient reduction of sperm counts at 7.5 mg/kg.

Methods: The safety profile of the compound of Example 1 was assessed invitro with target selectivity (cell-based luciferase assays), off-targetscreening (e.g., patch clamp and cAMP assays), and genotoxicity (Amestest) studies. Acute toxicity in animals was studied with single doseexperiments in mice, rats, and dogs. Dose range finding (DRF) studies inrats and dogs were performed to evaluate sub chronic toxicity over a14-Day dosing period.

Results: The compound of Example 1 is highly selective for RAR-alpha(the respective IC₅₀ of the compound of Example 1 was 6.7 nM againstRAR-alpha and >3,700 nM against RAR-beta and RAR-gamma), is notconsidered a hERG inhibitor (the IC₅₀ was >30 PM) and has no genotoxicpotential (negative Ames test). Single dose studies showed that therespective maximum tolerated dose in mice, rats and dogs was >1,000mg/kg, 750 mg/kg and >500 mg/kg. Repeated dosing for 14 daysdemonstrated that rats and dogs tolerated 50-75 mg/kg and 25 mg/kg,respectively. Using simple dose conversion, these values represent13-20× and 22× multiples over mouse efficacy (7.5 mg/kg).

Conclusions: The compound of Example 1 has demonstrated potent andreversible efficacy in mice and an initial safety profile with an atleast 10× safety margin in rats and dogs.

Example 19. In Vivo Studies of Reversing Infertility

Mouse studies with sperm count as readout: In an initial study, 25sexually mature male CD-1 mice were dosed with 10 mg/kg/day for 4 weeksthat resulted in a 90% reduction of epididymal sperm counts to0.51±0.27×10⁷ as assessed 24 h after administering the last dose. Dosingwas stopped on Day 29. Sperm counts started to increase over theremaining 2 weeks supporting reversibility of the effect (FIG. 7 ).Study 2: Subsequent efficacy studies with 7.5 mg/kg of the compound ofExample 1 were performed to determine the minimum efficacious dose inmice. Dosing 40 sexually mature male CD-1 mice with 7.5 mg/kg/day for 4weeks resulted in an 86% reduction of epididymal sperm counts to0.82±0.45×10⁷ as assessed 24 h after administering the last dose. Dosingwas stopped on Day 29. Sperm counts started to increase over theremaining 2 weeks supporting reversibility of the effect (FIG. 8 ). Freeserum testosterone levels were also determined in the animals dosed at7.5 mg/kg/day. Free testosterone levels did not significantly changeduring the dosing and recovery period in dosed animals compared tocontrol animals (FIG. 9 ).

Cynomolgus macaque study with sperm concentration as readout: The designof the study is to daily dose sexually mature male cynomolgus macaqueswith the compound of Example 1 until sperm counts per ejaculate drop tobelow 200 million sperm cells per ejaculate. Cynomolgus macaques with130±70 million sperm per ejaculate are considered poor candidates forbreeding programs compared to 734±136 million sperm per ejaculatereported from successful breeders. Sperm counts were assessed weekly orbi-weekly in fresh semen samples obtained with electroejaculation. 3macaques were orally dosed with 2.5 mg/kg, which is the dose equivalentto 10 mg/kg in mouse based on body surface area. Over a dosing period of54 days, individual sperm counts decreased to 27, 175 and 31×10⁶. Theanimals are now in recovery to assess reversibility (data not shown). Asecond cohort of 3 male cynomolgus macaques was dosed with 5 mg/kg/dayof the compound of Example 1 for 30 days followed by 7.5 mg/kg/day for 1week. Initial individual sperm counts of 598, 203 and 277×10⁶ decreasedto 377, 62 and 134×10⁶ after 14 days, and to 262, 28 and 70×10⁶ after 30days of dosing with 5 mg/kg/day showing efficacy in animal #1 and animal#3 (FIG. 10 ). After dosing for another week at 7.5 mg/kg/day,individual sperm counts were 132, 38 and 12×10⁶ showing efficacy in all3 animals. Since day 38, the animals have been in recovery to assessreversibility. Four weeks after the animals received the last dose,individual sperm counts were 297, 71 and 300×10⁶ showing 50%reversibility in animal #1, 65% reversibility in animal #2 and 100%reversibility in animal #3.

Rat and dog studies: In male Sprague-Dawley rats and male Beagle dogsthat received various daily doses of the compound of Example 1 for 14days in a repeat dose toxicity study (see Example 22), histopathologyshowed the degeneration of the germinal epithelium in the testis. Theeffect was visible in all evaluated tubuli seminiferi contorti of dogtestis slides and in a subset of evaluated tubuli seminiferi contorti ofrat testis slides (FIG. 11 ).

Example 20. Pharmacokinetics (PK) Studies

Single dose pharmacokinetics (PK) studies at therapeutic dose levels:Presented are area under the curve (AUC) values to better compareexposure levels between species.

Mouse study: 15 sexually mature male CD-1 mice received a single 10mg/kg dose of the compound of Example 1, which demonstratedcontraceptive efficacy in an initial study. AUC from time point 0extrapolated to infinite time (AUC_(0-inf)) in plasma was 6,681h*(ng/mL). This value serves as the basis to calculate multiples overefficacy across species.

NHP studies: Three young adult male marmosets received a single 5 mg/kgdose of the compound of Example land the compound of 3 sexually maturemale cynomolgus macaques received a single dose of 0.5, 1, 5 and 10mg/kg. Table 1 shows respective plasma AUC_(0-last) levels and multiplesover mouse exposure.

TABLE 1 AUC_(0-inf) levels and multiples over mouse exposure inmarmosets and cynomolgus macaques (cyno). Mouse Marmoset Cyno Cyno CynoCyno 10 mg/kg 5 mg/kg 0.5 mg/kg 1 mg/kg 5 mg/kg 10 mg/kg Mouseequivalent dose — 10 mg/kg 2 mg/kg 4 mg/kg 20 mg/kg 40 mg/kg AUC_(0-inf)(h*ng*mL⁻¹) 6,681 6,920 23,382 33,394 175,202 293,423 Multiple overmouse exposure — 1X 3.5X 5X 26X 44X

Repeat Dose PK Studies at Supratherapeutic Dose Levels:

Rat study: Male Sprague-Dawley rats (7-9 weeks old) received 0, 25, 50and 125 mg/kg/day of the compound of Example 1 (3 rats per group) for 14days. Since 125 mg/kg/day was not tolerated well, the dose was reducedto 75 mg/kg on Day 7. In this study, the AUC from time point 0 to thetime of the last measured concentration (48 h) was measured (AUC₀₋₄₈).Table 2 shows plasma AUC₀₋₄₈ levels on Day 14 and multiples over mouseexposure.

TABLE 2 AUC₀₋₄₈ levels on Day 14 and multiples over mouse exposure inrats after a 14-day dosing period. Rat Mouse Rat Rat 125/75 10 mg/kg 25mg/kg 50 mg/kg mg/kg Mouse equivalent — 50 mg/kg 100 mg/kg 250/150 dosemg/kg AUC₀₋₄₈ (h*ng*mL⁻¹) 6,577 78,778 91,122 202,091 Multiple overmouse — 12X 14X 3IX* exposure *This is related to 75 mg/kg.

Dog study Two male Beagle dogs (8-12 months old) received 0, 25 and 100mg/kg/day of the compound of Example 1 for 14 days. In this study,AUC_(0-inf) was measured. Table 3 shows plasma AUC_(0-last) levels onDay 14 and multiples over mouse exposure

TABLE 3 AUC_(0-inf) levels on Day 14 and multiples over mouse exposurein dogs after a 14-day dosing period. Mouse Dog Dog 10 mg/kg 25 mg/kg100 mg/kg Mouse equivalent dose — 167 mg/kg 667 mg/kg AUC_(0-inf)(h*ng*mL⁻¹) 6,681 751,730 14,128,277 Multiple over mouse exposure — 113X2,115X \

Example 21. In Vitro Studies

The following Table 4 summarizes in vitro study results for the compoundof Example 1.

TABLE 4 The compound of Example 1 in vitro studies Solubility Up to 100mg/mL in saline and >100 mg/mL in 50% carbitol [2-(2-ethoxyethoxy)ethanol LogD 3.5 Target The respective half-maximalinhibitory concentration (IC₅₀) of the compound of selectivity: Example1 was 6.7 nM against retinoic acid receptor (RAR)-alpha and >3,700 nMagainst RAR-beta and RAR-gamma. hERG: The compound of Example 1 is notconsidered an hERG inhibitor. The IC₅₀ in hERG-transfected HEK293 cellswas >30 μM. Antagonist Agonist and antagonist activity of the compoundof Example 1 was tested against 48 activity against potentialoff-targets including 6 ion channels, 17 non-nuclear receptors, 2 ionchannels, transporters, 11 enzymes, and 2 nuclear receptors. At 10 μMthe compound of transporters, Example 1 had agonist or antagonistactivity of <10% against 39 of them (including enzymes andglucocorticoid and androgen receptors). The following 10 targets wereinhibited by nuclear receptors: at least 10% with 10 μM of the compoundof Example 1: 1) acetylcholinesterase (AChE) by 10.2%, 2) Kir2.1(potassium channel of excitable cells) by 13.2%, 3) KVLQT(7.1)/mink(cardiac potassium ion channel) by 14.9%, 4) KCNQ1 (neuronal potassiumion channel) by 22.8%, 5) cannabinoid receptor 2 (CB2) by 34.3%, 6)NaV1.5 (cardiac sodium ion channel) by 37.4%, 7) monoamine oxidase A(MAO-A) by 45.8%, 8) cyclooxygenase 2 (COX2) by 61.8%, 9) cyclooxygenase1 (COX1) by 78.9% and 10) cannabinoid receptor 1 (CB1) by 90.5%. Therespective IC₅₀ values were: 1.41 μM (COX1), 1.8 μM (CB1), 8.51 μM(COX2), 8.8 μM (NaV1.5), >10 μM (Kir2.1), 23.3 μM (CB2), 24.6 μM(MAO-A), and >30 μM (AChE). The IC₅₀ against KCNQ1 was not determined.Ames test: The results showed no indication that the compound of Example1 has genotoxic potential. The stability of the compound of Example 1was assessed in mammalian hepatocytes and liver microsomes. Shown beloware the respective half-lives (T_(1/2)). Hepatocytes Liver microsomes(Phase 1 and Phase II metabolism) (Phase I metabolism) Stability inhuman 8.7 h    9.5 h hepatocytes and monkey 3.2 h   23.1 h liver micro-mouse 4.8 h >23.1 h somes: rat 7.9 h >23.1 h rabbit not tested   19.6 hdog >10 h  >23.1 h MetID Under the experimental conditions, very littlemetabolism of the compound of Example 1 occurred in hepatocytes ofvarious mammalian species (human, monkey, mouse, rat, dog, and rabbit)and neither of the ten metabolites was detected at greater than 10% oftotal metabolites. Cytotoxicity: The compound of Example 1 showed nocytopathic effects in HepG2 and human lung fibroblast assays.

Example 22. Toxicity Studies Single Dose Toxicity:

The respective maximum tolerated dose (MTD) of the compound of Example 1in male CD-1 mice, Sprague-Dawley rats and Beagle dogs was ≥1,000 mg/kg,≥750 mg/kg and ≥500 mg/kg. These were the respective highest dose levelstested.

Repeat Dose Toxicity at Therapeutic Levels:

Mouse: 40 sexually mature male CD-1 mice received 7.5 and 10 mg/kg/dayof the compound of Example 1, respectively, for 4 weeks. All dosedanimals behaved normally, had no changes in body weight, CBC parametersor clinical chemistry parameters compared to control animals.

Non-human primate: All 6 male cynomolgus macaques of the efficacystudies behaved normally and had no substantial changes in body weight,CBC parameters or clinical chemistry parameters.

Repeated Dose Toxicity at Supratherapeutic Levels

14-day dose range finding (DRF) study with rats: Male Sprague-Dawleyrats (7-9 weeks old) received 0, 25, 50, 125 and 250 mg/kg/day of thecompound of Example 1 (5 rats per group) via oral gavage. 25 and 50mg/kg were tolerated well. Initial dosing with 125 mg/kg was nottolerated well so that the dose was reduced to 75 mg/kg for theremaining 8 days. Over that period the animals' overall health andactivity improved, they gained weight, and had normal CBC and clinicalchemistry. 250 mg/kg/day was not tolerated. These results show that themaximum tolerated dose over a 2-week dosing period was 50 mg/kg. 14-dayDRF study with dogs: Male Beagle dogs (8-12 months old) received 0, 25,50 and 100 mg/kg/day of the compound of Example 1 (2 dogs per group) viaoral gavage. 25 mg/kg were tolerated well and both animals behavednormally and did not show signs of toxicity. 50 mg/kg was not tolerated.In the 100 mg/kg group one dog did not show any signs of toxicity. Theother dog lost weight as of Day 12 until termination. Based on theseresults, the maximum tolerated dose over a 2-week dosing period was 25mg/kg.

Example 23. Synthesis of4-(5-(4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen-6-yl)-1H-pyrrol-2-yl)benzoicAcid

a. Preparation of tert-butyl2-(4-(methoxycarbonyl)phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate

Under a nitrogen atmosphere, (Boc)₂O (20.0 mL, 1 M in DCM, 2.1 equiv)was added to a solution of methyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-yl)benzoate(3.20 g, 9.72 mmol, 1.0 equiv) and DMAP (60 mg, 0.49 mmol, 0.05 equiv)in dry MeCN (5 mL) at room temperature. The mixture was stirred untilthe starting material disappeared completely. After water was added, theresulting mixture was extracted with DCM (20 mL×3). The organic phasewas washed with brine, dried over Na₂SO₄, and evaporated under reducedpressure. The residue was purified by flash column chromatography (SiO₂,100% hexanes to 10% EtOAc in hexanes) to give the product (2.34 g, 56%)as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.04-7.97 (m, 2H),7.40-7.34 (m, 2H), 6.64 (d, J=3.3 Hz, 1H), 6.25 (d, J=3.3 Hz, 1H), 3.92(s, 3H), 1.35 (s, 12H), 1.32 (s, 9H).

b. Preparation of tert-butyl2-(2,2-dimethyl-4-oxochroman-6-yl)-5-(4-(methoxy-carbonyl)phenyl)-1H-pyrrole-1-carboxylate

6-Bromo-2,2-dimethylchroman-4-one (550 g, 2.16 mmol, 1.1 equiv),tert-butyl2-(4-(methoxycarbonyl)phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate(822 mg, 1.92 mmol, 1.0 equiv), K₂CO₃ (830 mg, 6.01 mmol, 3.1 equiv)were taken into a round-bottom flask followed by addition of DME (15 mL)and H₂O (2 mL). Then N₂ was bubbled through the reaction mixture for 10min followed by addition of Pd(dppf)Cl₂.CH₂Cl₂ (160 mg, 0.196 mmol, 0.1equiv). Then the vial was sealed and placed in a preheated oil bath at90° C. and refluxed for 6 h. After the reaction was complete, brine wasadded to the reaction mixture and extracted with EtOAc (20 mL×3), driedover MgSO₄. The solvent was evaporated to dryness. The residue waspurified by flash column chromatography (SiO₂, 100% hexanes to 20% EtOAcin hexanes) to obtain the product as a white solid (600 mg, 66%). ¹H NMR(400 MHz, CDCl₃) δ 8.08-8.01 (m, 2H), 7.88 (d, J=2.3 Hz, 1H), 7.53 (dd,J=8.5, 2.3 Hz, 1H), 7.48-7.41 (m, 2H), 7.03-6.92 (m, 1H), 6.30 (d, J=3.4Hz, 1H), 6.23 (d, J=3.4 Hz, 1H), 3.93 (s, 3H), 2.74 (s, 2H), 1.48 (s,6H), 1.19 (s, 9H).

c. Preparation of tert-butyl2-(2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-2H-chromen-6-yl)-5-(4-(methoxycarbonyl)phenyl)-1H-pyrrole-1-carboxylate

To a stirred solution of tert-butyl2-(2,2-dimethyl-4-oxochroman-6-yl)-5-(4-(methoxycarbonyl)phenyl)-1H-pyrrole-1-carboxylate(583 mg, 1.23 mmol, 1.0 equiv), 2,6-lutidine (925 mg, 8.63 mmol, 7.0equiv) and DMAP (41 mg, 0.34 mmol, 0.3 equiv) in anhydrous DCM (10 mL)at 0° C. was added triflic anhydride (1.00 g, 3.54 mmol, 2.9 equiv)dropwise and the reaction mixture was slowly warmed to room temperaturewith continuous stirring. After stirring overnight at room temperature,the reaction was quenched with saturated sodium bicarbonate solution andextracted with DCM (20 mL×3). The combined organic layers were thenwashed with brine, dried over MgSO₄, filtered, and concentrated underreduced pressure to yield a crude brown oil. The crude product waspurified by flash column chromatography (SiO₂, 100% hexanes to 10% EtOACin hexanes) to obtain the product (550 mg, 77%) as a colorless liquid.¹H NMR (400 MHz, CDCl₃) δ 8.09-8.02 (m, 2H), 7.50-7.42 (m, 2H),7.32-7.23 (m, 2H), 6.86 (d, J=8.9 Hz, 1H), 6.31 (d, J=3.4 Hz, 1H), 6.21(d, J=3.4 Hz, 1H), 5.66 (s, 1H), 3.93 (s, 3H), 1.55 (s, 6H), 1.19 (s,9H).

d. Preparation of tert-butyl2-(4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen-6-yl)-5-(4-(methoxycarbonyl)phenyl)-1H-pyrrole-1-carboxylate

tert-Butyl2-(2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-2H-chromen-6-yl)-5-(4-(methoxycarbonyl)phenyl)-1H-pyrrole-1-carboxylate(200 g, 0.329 mmol, 1 equiv), (4-fluorophenyl)boronic acid (68 mg, 0.49mmol, 1.5 equiv), K₃PO₄ (4.0 mL 0.5 M in H₂O, 2.0 mmol, 6.1 equiv) wastaken into a round-bottom flask followed by addition of THE (2 mL). ThenN₂ was bubbled through the reaction mixture for 10 min followed by theaddition of XPhos Pd G2 (60 mg, 0.076 mmol, 0.2 equiv). Then the vialwas sealed and placed in a preheated block at 45° C. and stirred for 3h. After the reaction was complete, brine was added to the reactionmixture and extracted with EtOAc (5 mL×3), dried over MgSO₄, and thesolvent was evaporated under reduced pressure. The residue was purifiedby flash column chromatography (SiO₂, 100% hexanes to 20% EtOAc inhexanes) to obtain the product as a white solid (132 mg, 72%). ¹H NMR(400 MHz, CDCl₃) δ 8.09-7.99 (m, 2H), 7.45-7.38 (m, 2H), 7.37-7.28 (m,2H), 7.21 (dd, J=8.3, 2.2 Hz, 1H), 7.13-7.02 (m, 2H), 7.01 (d, J=2.1 Hz,1H), 6.91 (d, J=8.3 Hz, 1H), 6.27 (d, J=3.4 Hz, 1H), 6.14 (d, J=3.4 Hz,1H), 5.62 (s, 1H), 3.93 (s, 3H), 1.52 (s, 6H), 1.16 (s, 9H).

e. Preparation of methyl4-(5-(4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen-6-yl)-1H-pyrrol-2-yl)benzoate

tert-Butyl2-(4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen-6-yl)-5-(4-(methoxycarbonyl)phenyl)-1H-pyrrole-1-carboxylate(100 mg, 0.181 mmol, 1 equiv) was heated to 180° C. under N₂ gas for 30min. The dark residue was purified by flash column chromatography toobtain the product (62 mg, 76%) as a white powder. ¹H NMR (400 MHz,CDCl₃) δ 8.52 (s, 1H), 8.03 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.1 Hz, 2H),7.38 (td, J=5.4, 2.3 Hz, 3H), 7.18-7.10 (m, 3H), 6.96 (d, J=8.3 Hz, 1H),6.67 (t, J=3.2 Hz, 1H), 6.39 (t, J=3.2 Hz, 1H), 5.67 (s, 1H), 3.93 (s,3H), 1.54 (s, 6H).

f. Preparation of4-(5-(4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen-6-yl)-1H-pyrrol-2-yl)benzoicAcid

To a solution of methyl4-(5-(4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen-6-yl)-1H-pyrrol-2-yl)benzoate(50 mg, 0.11 mmol, 1.0 equiv) in THE (1 mL) and MeOH (1 mL), was addedLiOH (50 mg, 1.2 mmol, 11 equiv) dissolved in water (1 mL) and theresulting mixture was stirred overnight at room temperature. Then theorganic layer was evaporated under reduced pressure and the aqueoussuspension was acidified with 2N HCl to reach pH 1.0. Then the reactionmixture was extracted with EtOAc (2 mL×3), washed with brine, and driedover MgSO₄. The extract was purified by flash column chromatography(SiO₂, 100% hexanes to 50% EtOAc and 2% HCOOH in hexanes) to obtain theproduct (36 mg, 74%) as a yellow solid. ¹H NMR (400 MHz, THF-d₈) δ 10.40(s, 1H), 7.96-7.89 (m, 2H), 7.64-7.57 (m, 2H), 7.50-7.36 (m, 3H), 7.27(d, J=2.2 Hz, 1H), 7.21-7.12 (m, 2H), 6.86 (d, J=8.4 Hz, 1H), 6.60 (dd,J=3.7, 2.5 Hz, 1H), 6.27 (dd, J=3.7, 2.4 Hz, 1H), 5.72 (s, 1H), 1.46 (s,6H).

Example 24. Synthesis of Representative Compounds

Using procedures similar to those described above, the followingcompounds were prepared.

Example 25. Biological Activity

Representative compounds of the invention were evaluated in the assaydescribed in Example 13 to provide the following data.

RARα RARβ RARγ Antagonism Antagonism Antagonism Compound IC₅₀ (nM) IC₅₀(nM) IC₅₀ (nM)

       6.8 >3700 >3700

  100

  470

  736

  773

  943

>3300

 2000

>3300

   15 >3300 >3300

   44 >3000 >3000

  466 >3000 >3000

   94 >3000 >3000

 1306 >3000 >3000

  368 >3000 >3000

>3300 >3000 >3000

  811 >3000 >3000

   87 >3000 >3000

>3000 >3000 >3000

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, C₁-C₃alkyl, or haloC₁-C₃ alkyl; R² is H, C₁-C₃ alkyl, or haloC₁-C₃ alkyl; R³is C₆-C₁₀ aryl, 5-10 membered heteroaryl, C₆-C₁₀ arylC₁-C₃ alkyl, or5-10 membered heteroarylC₁-C₃ alkyl, wherein any C₆-C₁₀ aryl, 5-10membered heteroaryl, C₆-C₁₀ arylC₁-C₃ alkyl, and 5-10 memberedheteroarylC₁-C₃ alkyl is optionally substituted with one or more groupsindependently selected from halo, cyano, nitro, carboxy, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ alkanoyl, C₁-C₆ alkanoyloxy, C₁-C₆ alkoxycarbonyl,—NR^(a)R^(b), and —C(═O)NR^(c)R^(d), wherein any C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ alkanoyl, C₁-C₆ alkanoyloxy, and C₁-C₆ alkoxycarbonyl isoptionally substituted with one or more groups independently selectedfrom halo; R⁴ is C₆-C₁₀ aryl, 5-10 membered heteroaryl, C₆-C₁₀ arylC₁-C₃alkyl, or 5-10 membered heteroarylC₁-C₃ alkyl, wherein any C₆-C₁₀ aryl,5-10 membered heteroaryl, C₆-C₁₀ arylC₁-C₃ alkyl, and 5-10 memberedheteroarylC₁-C₃ alkyl is substituted with carboxy and is furtheroptionally substituted with one or more groups independently selectedfrom halo, cyano, nitro, carboxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆alkanoyl, C₁-C₆ alkanoyloxy, C₁-C₆ alkoxycarbonyl, —NR^(e)R^(f), and—C(═O)NR^(g)R^(h), wherein any C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆alkanoyl, C₁-C₆ alkanoyloxy, and C₁-C₆ alkoxycarbonyl is optionallysubstituted with one or more groups independently selected from halo; R⁵is H, C₁-C₃ alkyl, hydroxy, C₁-C₃ alkoxy, halo or haloC₁-C₃ alkyl; R⁶ isH, C₁-C₃ alkyl, hydroxy, C₁-C₃ alkoxy, halo or haloC₁-C₃ alkyl; eachR^(a) and R^(b) is independently selected from the group consisting ofH, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, and(C₃-C₆)cycloalkyl(C₁-C₆)alkyl; or R^(a) and R^(b) together with thenitrogen to which they are attached form an aziridino, azetidino,morpholino, piperazino, pyrrolidino or piperidino ring, which ring isoptionally substituted with one or more groups independently selectedfrom C₁-C₆ alkyl and haloC₁-C₆ alkyl; each R^(c) and R^(d) isindependently selected from the group consisting of H, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, and (C₃-C₆)cycloalkyl(C₁-C₆)alkyl;or R^(c) and R^(d) together with the nitrogen to which they are attachedform an aziridino, azetidino, morpholino, piperazino, pyrrolidino orpiperidino ring, which ring is optionally substituted with one or moregroups independently selected from C₁-C₆ alkyl and haloC₁-C₆ alkyl; eachR^(e) and R^(f) is independently selected from the group consisting ofH, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, and(C₃-C₆)cycloalkyl(C₁-C₆)alkyl; or R^(e) and R^(f) together with thenitrogen to which they are attached form an aziridino, azetidino,morpholino, piperazino, pyrrolidino or piperidino ring, which ring isoptionally substituted with one or more groups independently selectedfrom C₁-C₆ alkyl and haloC₁-C₆ alkyl; and each R^(g) and R^(h) isindependently selected from the group consisting of H, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, and (C₃-C₆)cycloalkyl(C₁-C₆)alkyl;or R^(g) and R^(h) together with the nitrogen to which they are attachedform an aziridino, azetidino, morpholino, piperazino, pyrrolidino orpiperidino ring, which ring is optionally substituted with one or moregroups independently selected from C₁-C₆ alkyl and haloC₁-C₆ alkyl. 2.The compound or pharmaceutically acceptable salt of claim 1, wherein R¹is C₁-C₃ alkyl.
 3. The compound or pharmaceutically acceptable salt ofclaim 1, wherein R¹ is methyl.
 4. The compound or pharmaceuticallyacceptable salt of claim 1, wherein R² is C₁-C₃ alkyl.
 5. The compoundor pharmaceutically acceptable salt of claim 1, wherein R² is methyl. 6.The compound or pharmaceutically acceptable salt of claim 1, wherein R³is C₆-C₁₀ aryl that is optionally substituted with one or more groupsindependently selected from halo, cyano, nitro, carboxy, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ alkanoyl, C₁-C₆ alkanoyloxy, C₁-C₆ alkoxycarbonyl,—NR^(a)R^(b), and —C(═O)NR^(c)R^(d), wherein any C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ alkanoyl, C₁-C₆ alkanoyloxy, and C₁-C₆ alkoxycarbonyl isoptionally substituted with one or more groups independently selectedfrom halo.
 7. The compound or pharmaceutically acceptable salt of claim1, wherein R³ is phenyl that is optionally substituted with one or moregroups independently selected from halo, cyano, nitro, carboxy, C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ alkanoyl, C₁-C₆ alkanoyloxy, C₁-C₆alkoxycarbonyl, —NR^(a)R^(b), and —C(═O)NR^(c)R^(d), wherein any C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ alkanoyl, C₁-C₆ alkanoyloxy, and C₁-C₆alkoxycarbonyl is optionally substituted with one or more groupsindependently selected from halo.
 8. The compound or pharmaceuticallyacceptable salt of claim 1, wherein R³ is C₆-C₁₀ aryl that is optionallysubstituted with one or more groups independently selected from C₁-C₆alkyl that is optionally substituted with one or more groupsindependently selected from halo.
 9. The compound or pharmaceuticallyacceptable salt of claim 1, wherein R³ is phenyl that is optionallysubstituted with one or more groups independently selected from C₁-C₆alkyl that is optionally substituted with one or more groupsindependently selected from halo.
 10. The compound or pharmaceuticallyacceptable salt of claim 1, wherein R³ is C₆-C₁₀ aryl that issubstituted with C₁-C₆ alkyl.
 11. The compound or pharmaceuticallyacceptable salt of claim 1, wherein R³ is phenyl that is substitutedwith C₁-C₆ alkyl.
 12. The compound or pharmaceutically acceptable saltof claim 1, wherein R³ is 4-methylphenyl.
 13. The compound orpharmaceutically acceptable salt of claim 1, wherein R⁴ is C₆-C₁₀ arylthat is substituted with carboxy and that is further optionallysubstituted with one or more groups independently selected from halo,cyano, nitro, carboxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkanoyl, C₁-C₆alkanoyloxy, C₁-C₆ alkoxycarbonyl, —NR^(a)R^(b), and —C(═O)NR^(c)R^(d),wherein any C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkanoyl, C₁-C₆alkanoyloxy, and C₁-C₆ alkoxycarbonyl is optionally substituted with oneor more groups independently selected from halo.
 14. The compound orpharmaceutically acceptable salt of claim 1, wherein R⁴ is phenyl thatis substituted with carboxy and that is further optionally substitutedwith one or more groups independently selected from halo, cyano, nitro,carboxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkanoyl, C₁-C₆ alkanoyloxy,C₁-C₆ alkoxycarbonyl, —NR^(a)R^(b), and —C(═O)NR^(c)R^(d), wherein anyC₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkanoyl, C₁-C₆ alkanoyloxy, and C₁-C₆alkoxycarbonyl is optionally substituted with one or more groupsindependently selected from halo.
 15. The compound or pharmaceuticallyacceptable salt of claim 1, wherein R⁴ is C₆-C₁₀ aryl that issubstituted with carboxy and that is further optionally substituted withone or more groups independently selected from C₁-C₆ alkyl that isoptionally substituted with one or more groups independently selectedfrom halo.
 16. The compound or pharmaceutically acceptable salt of claim1, wherein R⁴ is phenyl that is substituted with carboxy and that isfurther optionally substituted with one or more groups independentlyselected from C₁-C₆ alkyl that is optionally substituted with one ormore groups independently selected from halo.
 17. The compound orpharmaceutically acceptable salt of claim 1, wherein R⁴ is C₆-C₁₀ arylthat is substituted with carboxy.
 18. The compound or pharmaceuticallyacceptable salt of claim 1, wherein R⁴ is phenyl that is substitutedwith carboxy.
 19. The compound or pharmaceutically acceptable salt ofclaim 1, wherein R⁴ is 4-carboxyphenyl.
 20. The compound orpharmaceutically acceptable salt of claim 1, wherein R⁵ is H.
 21. Thecompound or pharmaceutically acceptable salt of claim 1, wherein R⁶ isH.
 22. The compound or pharmaceutically acceptable salt of claim 1 thatis:

or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrugthereof.
 23. The compound or pharmaceutically acceptable salt of claim1, which is a compound of formula (Ia):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrugthereof.
 24. The compound or pharmaceutically acceptable salt of claim1, which is a compound of formula (Ib):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrugthereof.
 25. The compound or pharmaceutically acceptable salt of claim1, which is a compound of formula (Ic):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrugthereof.
 26. The compound or pharmaceutically acceptable salt of claim1, which is a compound of formula (Id):

or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrugthereof.
 27. The compound or pharmaceutically acceptable salt of claim 1that is:

or a pharmaceutically acceptable salt, stereoisomer, solvate, or prodrugthereof.
 28. The compound or pharmaceutically acceptable salt of claim 1that is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 29. A pharmaceuticalcomposition comprising a compound or pharmaceutically acceptable salt asdescribed in claim 1, and a pharmaceutically acceptable excipient.
 30. Amethod to reduce sperm count in a male subject, to produce reversibleinfertility in a male subject or reduce the likelihood of conceptionfollowing intercourse between a male subject and a female subjectcomprising administering a compound or pharmaceutically acceptable saltas described in claim 1 to the male subject. 31-32. (canceled)
 33. Amethod for treating a disease or condition associated with RAR alphaactivity in a subject wherein antagonism of RAR alpha is indicated,comprising administering a compound or pharmaceutically acceptable saltas described in claim 1 to the subject.
 34. A method for selectivelyantagonizing RAR alpha over RAR beta and RAR gamma in a subject,comprising administering a compound or pharmaceutically acceptable saltas described in claim 1 to the subject.
 35. (canceled)
 36. A compound orpharmaceutically acceptable salt as described in claim 1 for use inmedical therapy, wherein the medical therapy is selected from the groupconsisting of reducing sperm count in a male subject, producingreversible sterility in a male subject, reducing the likelihood ofconception following intercourse between a male subject and a femalesubject, treating a disease or condition associated with RAR alphaactivity. 37-40. (canceled)
 41. A compound or pharmaceuticallyacceptable salt as described in claim 1 to selectively antagonize RARalpha over RAR beta and RAR gamma in vitro. 42.-47. (canceled)